CN104230827A - 1-(aryl methyl) quinazoline-2,4(1H,3H) diketone used as PARP (Poly-ADP-Ribose Polymerase) inhibitor and application thereof - Google Patents

1-(aryl methyl) quinazoline-2,4(1H,3H) diketone used as PARP (Poly-ADP-Ribose Polymerase) inhibitor and application thereof Download PDF

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CN104230827A
CN104230827A CN201410398758.5A CN201410398758A CN104230827A CN 104230827 A CN104230827 A CN 104230827A CN 201410398758 A CN201410398758 A CN 201410398758A CN 104230827 A CN104230827 A CN 104230827A
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carbonyl
quinazoline
diketone
benzyl
piperazine
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CN104230827B (en
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蔡遂雄
田野
董海军
许庆兵
吴利珍
刘丽军
江洋珍
鲍庆立
王国相
殷峰
顾诚云
胡秀华
王晓珠
康思顺
陈圣志
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Shanghai junpaiyingshi Pharmaceutical Co.,Ltd.
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NANJING THERAPEUTICS Inc
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Abstract

The invention provides novel 1-(aryl methyl) quinazoline02,4(1H,3H) diketone which is as shown in the formula I in the specification, and in the formula I, Ar and R1-R6 are defined in the specification. The compound as shown in the formula I is a PARP (Poly-ADP-Ribose Polymerase) inhibitor. Therefore, the compound provided by the invention can be used for treating diseases caused by PARP activity abnormity.

Description

1-(arylmethyl) quinazoline-2,4 (1H, 3H)-diketone is as PARP inhibitor and application thereof
The application is international application no is PCT/CN2012/073362, international filing date is on March 31st, 2012, the application number entering National Phase in China is 201280001822.0, name is called the divisional application of the application for a patent for invention of " 1-(arylmethyl) quinazoline-2; 4 (1H, 3H)-diketone is as PARP inhibitor and application thereof ".
Technical field
The invention belongs to medicinal chemistry art.The present invention be more particularly directed to 1-(arylmethyl) quinazoline-2,4 (1H, 3H)-diketone, and as upper effective poly (ADP-ribose) polysaccharase (PARP) inhibitor for the treatment of, and the application of cancer therapy drug.
Background technology
Poly (ADP-ribose) polysaccharase (poly (ADP-ribose) polymerase, PARP) catalysis adds poly (ADP-ribose) by NAD+ on target protein molecule, is the important component part of DNA plerosis process.This process, to maintenance DNA and chromosomal complete and stablize most important, is ensure the important leverage of mammalian cell survival.Intracellular most ADP-ribose polymerization vigor is formed by PARP-1 catalysis, although PARP-2 and other hypotypes also have this function.The mouse knocking out PARP-1 does not possess single stranded DNA injury repairing function (Krishnakumar and Kraus, 2010, Molecular Cell39:8).Simultaneously, there is the cancer cells that DNA repairs disappearance function, such as BRCA1 (mammary cancer 1) or BRCA2 (mammary cancer 2) absence type cancer cells, to the anticancer chemotherapeutic agent causing DNA damage, comprise containing platinum-based chemotherapy medicine, DNA methylation class anticancer chemotherapeutic agent and DNA topoisomerase enzyme inhibitor class etc., or radiotherapy is especially responsive.It is effective (Andrew Tutt et al., 2009, J.Clin.Oncol27:18s that clinical second phase trial data presentation PARP-1 inhibitor Aura handkerchief Buddhist nun (olaparib, AZD2281) is used for the treatment of advanced breast cancer; Andrew Tutt et al., 2010Lancet376:235; RA Dent et al., 2010J.Clin.Oncol.28:15s).This series of science and clinical test results display PARP-1 inhibitor can be used as cancer therapy drug and effectively treat kinds cancer.Therapeutic cancer is carried out mainly based on two kinds of mechanism with PARP-1 inhibitor.One, due to quick growth, cancer cell DNA replication dna is far away higher than normal cell.Therefore the medicine of DNA damage can be caused to cause the death of cancer cells selectively.But because DNA repair enzyme is as the existence of PARP-1, the property of medicine of this kind of medicine can not give full play to.Therefore PARP-1 inhibitor is combined with conventional DNA damage based chemotherapy cancer therapy drug, due to the suppression that it is repaired DNA, greatly be exaggerated DNA damage kind anti-cancer drugs thing, such as the property of medicine of Temozolomide (temozolamide), thus produce synergistic effect.Its two, to the cancer cells having DNA rectification of defects, the such as cancer cells such as triple negative breast cancer of BRCA1 or BRCA2 disappearance, PARP-1 inhibitor independently as cancer therapy drug, can directly kill these cells.Approximately the mammary cancer of 10-15% has the factor of family history heredity according to statistics, and the mammary cancer wherein caused due to BRCA1 or BRCA2 transgenation accounts for the 15-20% of all hereditary breast cancer.Repair because PARP-1 participates in DNA, application PARP-1 inhibitor suppresses the reparation of DNA to can be used for the cancer of effectively treating heredity DNA rectification of defects selectively, comprises triple negative breast cancer.PARP-1 inhibitor also can be used for treating the disease caused because cell transition is dead in addition, comprise the central nervous system disease such as apoplexy and nerve degenerative diseases (Akinori Iwashita et al., 2004, J.Pharmacol.Exp.Thera.310:425).
The available PARP-1 enzyme of activity of PARP-1 inhibitor directly measures.Simultaneously, because PARP-1 inhibitor can increase DNA damage based chemotherapy cancer therapy drug such as methyl mesylate (MMS) to the cytotoxicity of cancer cells, the activity of PARP-1 inhibitor also can use DNA damage kind anti-cancer drugs, such as MMS, under the existence of PARP-1 inhibitor, the cytotoxicity experiment mtt assay of cancer cells is measured.In addition, PARP-1 inhibitor is used alone and can have killed DNA rectification of defects, as BRCA1 or BRCA2 genetically deficient, and the tumour cell of three negative breast cancer.Therefore, the antitumour activity of PARP-1 inhibitor, can be measured by the inhibition of these compounds to the CAPAN-1 growth of pancreatic cancer cells that BRCA-2 lacks.
Known many cancer therapy drugs can cancer cell specific induction of apoptosis.Apoptosis Mechanism comprises the activation of a series of apoptotic proteins enzyme (caspases).Apoptotic proteins enzyme is one group of P needing substrate 1position is the L-Cysteine HCL Anhydrous family that aspartic acid residue could effectively be hydrolyzed.Wherein caspase-3 ,-6 and-7 is crucial apoptotic proteins enzymes, and they can cut the protein substrate in various kinds of cell, cause apoptosis.Intracellular apoptotic proteins enzymic activity can adopt fluorescently-labeled substrate to measure, for detecting apoptosis.PARP-1 inhibitor can increase the cell death inducing effect of DNA damage based chemotherapy cancer therapy drug such as MMS.Therefore the activity of PARP-1 inhibitor also can share the apoptotic proteins enzyme activity of inducing in cancer cells with DNA damage based chemotherapy cancer therapy drug and PARP-1 inhibitor and tests to measure.
JP2007137818 discloses preparation 8-hydroxyquinazoline-2,4 (1H, 3H)-derovatives as PARP inhibitor.Wherein X=(CH 2) n; N=1-4; Y=H, NR 1r 2, 1,2,3,4-tetrahydro isoquinolyl, octahydro isoquinolyl, 1,3-dioxy-1,3-dihydro-2H-pseudoindoyl, 3-oxygen-3,4-dihydrobenzo [Isosorbide-5-Nitrae] oxazines base, pyridyl, benzyl, the 5-person N heterocycle that can merge arbitrarily that can be substituted and the aryloxy etc. that can be substituted.
WO2006003148 discloses and prepares quinazolinedione derivatives as PARP inhibitor, for the treatment of the disease of PARP mediation.Wherein X and Y is N or CH independently; L 1be a key or alkyl; L 2be a tendon, CO, alkyl, CO-alkyl etc.; R 1for H or OH; Z is H, the aryl that can be substituted or heteroaryl etc.
Summary of the invention
As structural formula I, shown in formula II and formula III, the invention provides novel 1-(arylmethyl) quinazoline-2,4 (1H, 3H)-diketone as PARP inhibitor.
Present invention also offers the formula I comprising a significant quantity, the medicinal compositions of formula II or formula III compound, be used for Therapeutic cancer.
In one embodiment, described medicinal compositions also can contain one or more pharmaceutically acceptable carrier or thinner, is used for Therapeutic cancer.
In one embodiment, described medicinal compositions also can pharmacologically acceptable salt containing the known cancer therapy drug of at least one or described cancer therapy drug, is used for Therapeutic cancer.
The present invention also relates to structural formula I, the preparation method of the compounds of formula II and formula III.
Embodiment
Such as formula I, shown in formula II and formula III, the present invention finds that novel 1-(arylmethyl) quinazoline-2,4 (1H, 3H)-diketone can be used as efficient PARP inhibitor.
Specifically, compound used in the present invention is formula I or its pharmacologically acceptable salt or prodrug:
Wherein, Ar is the heteroaryl that the aryl that can be substituted maybe can be substituted;
R 1-R 6independent is hydrogen, halogen, the amino that can be substituted, the alkoxyl group that can be substituted, the C that can be substituted 1-10the alkylthio that alkyl, alkylhalide group, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, nitro, cyano group, amide group, hydroxyl, sulfydryl, acyloxy, azido-, carboxyl, ethylidene dioxy base, oxyamide base maybe can be substituted.
In preferred formula I, Ar is the phenyl, pyridyl or the furyl that are optionally substituted.More preferred Ar be between position have substituted carbonyl or methyl, have the phenyl of substituted carbonyl, pyridyl or furyl especially.R in preferred type I compound 5and R 6be all hydrogen.
Preferred compound of the present invention wherein one group be expressed as formula II compound or pharmaceutically acceptable salt thereof or prodrug:
Wherein, R 1-R 4independent is hydrogen, halogen, the amino that can be substituted, the alkoxyl group that can be substituted, the C that can be substituted 1-10the alkylthio that alkyl, alkylhalide group, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, nitro, cyano group, amide group, hydroxyl, sulfydryl, acyloxy, azido-, carboxyl, ethylidene dioxy base, oxyamide base maybe can be substituted.
R 7-R 10independent is hydrogen, halogen, the amino that can be substituted, alkoxyl group, C 1-10alkyl, alkylhalide group, aryl, heteroaryl, carbocylic radical, heterocyclic radical, alkenyl, alkynyl, arylalkyl, aromatic yl alkenyl, aromatic yl polysulfide yl, heteroarylalkyl, heteroarylalkenyl groups, heteroaryl alkynyl, carbocyclic ring alkyl, Heterocyclylalkyl, hydroxyalkyl, hydroxy alkoxy base, aminoalkyl, amido alkoxyl group, carboxyalkyl, Carboxyalkoxy, nitro, cyano group, amide group, aminocarboxyl, hydroxyl, sulfydryl, acyloxy, azido-, carboxyl, oxyamide base, alkyl sulphonyl, amido alkylsulfonyl, two substituted alkyl amido alkylsulfonyls, alkyl sulphinyl, the carbonyl of alkylthio or replacement.
R 11for amino, diazanyl, alkoxyl group, the C that can be substituted 1-10alkyl, alkylhalide group, aryl, heteroaryl, carbocylic radical, heterocyclic radical, alkenyl, alkynyl, arylalkyl, aromatic yl alkenyl, aromatic yl polysulfide yl, heteroarylalkyl, heteroarylalkenyl groups, heteroaryl alkynyl, carbocyclic ring alkyl, Heterocyclylalkyl, hydroxyalkyl, hydroxy alkoxy base, aminoalkyl, amido alkoxyl group, carboxyalkyl, Carboxyalkoxy, amide group, hydroxyl, sulfydryl, acyloxy, oxyamide base or alkylthio.
R in one group of preferred formula II compound 7, R 8, R 9or R 10hydrogen or halogen, particularly fluorine.Another organizes in preferred formula II compound, R 1or R 2hydrogen, fluorine, chlorine, bromine or methyl.Another organizes in preferred formula II compound, R 4hydrogen, fluorine, methyl, methoxyl group or hydroxyl.Another organizes in preferred formula II compound, R 11the amino replaced, the piperazine more preferably replaced or piperidines.
Preferred compound of the present invention wherein one group be expressed as formula III compound or pharmaceutically acceptable salt thereof or prodrug:
Wherein, R 1-R 4independent is hydrogen, halogen, the amino that can be substituted, the alkoxyl group that can be substituted, the C that can be substituted 1-10the alkylthio that alkyl, alkylhalide group, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, nitro, cyano group, amide group, hydroxyl, sulfydryl, acyloxy, azido-, carboxyl, ethylidene dioxy base, oxyamide base maybe can be substituted.
R 7-R 10independent is hydrogen, halogen, the amino that can be substituted, alkoxyl group, C 1-10alkyl, alkylhalide group, aryl, heteroaryl, carbocylic radical, heterocyclic radical, alkenyl, alkynyl, arylalkyl, aromatic yl alkenyl, aromatic yl polysulfide yl, heteroarylalkyl, heteroarylalkenyl groups, heteroaryl alkynyl, carbocyclic ring alkyl, Heterocyclylalkyl, hydroxyalkyl, hydroxy alkoxy base, aminoalkyl, amido alkoxyl group, carboxyalkyl, Carboxyalkoxy, nitro, cyano group, amide group, aminocarboxyl, hydroxyl, sulfydryl, acyloxy, azido-, carboxyl, oxyamide base, alkyl sulphonyl, amido alkylsulfonyl, two substituted alkyl amido alkylsulfonyls, alkyl sulphinyl, the carbonyl of alkylthio or replacement.
R 12for the C that can be substituted 1-10alkyl, alkylhalide group, cycloalkyl, aryl, heteroaryl, carbocylic radical, heterocyclic radical, alkenyl, alkynyl, acyl group, arylalkyl, aromatic yl alkenyl, aromatic yl polysulfide yl, heteroarylalkyl, heteroarylalkenyl groups, heteroaryl alkynyl, carbocyclic ring alkyl, Heterocyclylalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, alkyl-carbonyl, naphthene base carbonyl, aryl carbonyl, Heteroarylcarbonyl, Heterocyclylcarbonyl, amino-carbonyl, alkyl sulphonyl, naphthene sulfamide base or amido alkylsulfonyl.
In one group of preferred formula III compound, R 12cycloalkyl, aryl, heteroaryl, carbocylic radical, heterocyclic radical, arylalkyl, heteroarylalkyl, carbocyclic ring alkyl, Heterocyclylalkyl, alkyl-carbonyl, naphthene base carbonyl, aryl carbonyl, Heteroarylcarbonyl or the Heterocyclylcarbonyl that can be substituted.Another organizes in preferred formula III compound, R 1or R 2hydrogen, fluorine, chlorine, bromine or methyl; R 4hydrogen, fluorine, methoxyl group or hydroxyl; R 7, R 8, R 9or R 10hydrogen or fluorine.
Formula I, formula II and the preferred COMPOUNDS EXAMPLE of formula III include but not limited to:
1-(3-methoxycarbonyl benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(3-carboxybenzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(3-(4-(pyridine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(3-(4-cyclohexylpiperazin-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(3-(4-([1,2,4] triazolo [4,3-b] pyridazine-6-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(3-(4-ethyl piperazidine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(3-(4-benzoyl piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(3-(4-(4-fluorobenzoyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(3-(4-(4-chlorobenzoyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(3-(4-(4-Bromophenacyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(3-(4-(4-methoxybenzoyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(3-(4-(tetrahydrochysene-2H-pyrans-4-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(3-(4-(cyclopentylcarbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(3-(4-(cyclopropyl carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(3-(4-(ethylsulfonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(3-(4-Acetylpiperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(3-(4-Phenylpiperidine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(3-(4-phenylpiperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(3-(4-(pyrazine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(the fluoro-3-methoxycarbonyl benzyl of 4-) quinazoline-2,4 (1H, 3H)-diketone;
1-(3-carbonyl-4-luorobenzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(the fluoro-3-of 4-(4-(cyclopentylcarbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(the fluoro-3-of 4-(4-(pyridine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(the fluoro-3-of 4-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(3-(4-(cyclohexyl-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(3-(4-(benzo [d] isothiazole-3-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(3-(4-(piperidin-1-yl) piperidines-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(3-(4-(pyridin-4-yl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(3-(4-(cyclobutyl carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(3-(4-(6-fluorobenzene is [d] isoxzzole-3-base also) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(3-(4-(thiophene-2-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(3-(4-(furans-2-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(3-(4-(furans-3-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(3-(4-(thiophene-3-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(3-(4-(pyridine-3-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(3-(4-(pyridine-2-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(3-(4-(pyridine-4-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(3-(4-Phenoxypiperidines-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(the fluoro-3-of 4-(4-(cyclopropyl carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(the fluoro-3-of 4-(4-(cyclohexyl-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(the fluoro-3-of 4-(4-(pyrazine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(the fluoro-3-of 4-(4-(benzo [d] isothiazole-3-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(the fluoro-3-of 4-(4-(cyclobutyl carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(the fluoro-3-of 4-(4-benzoyl piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(the fluoro-3-of 4-(4-(thiophene-2-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(the fluoro-3-of 4-(4-(furans-2-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(the fluoro-3-of 6-(4-(cyclopentylcarbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(the fluoro-3-of 6-(4-(cyclohexyl-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(the fluoro-3-of 6-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(the fluoro-3-of 6-(4-(pyridine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(the fluoro-3-of 6-(4-(thiophene-2-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(the fluoro-3-of 6-(4-(cyclobutyl carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(the fluoro-3-of 6-(4-(furans-2-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(the chloro-3-of 6-(4-(cyclopentylcarbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1-(the chloro-3-of 6-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(the chloro-3-of 6-(4-(cyclohexyl-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(the chloro-3-of 6-(4-(pyridine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(the chloro-3-of 2-(4-(cyclopentylcarbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(the chloro-3-of 2-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(the fluoro-3-of 2-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(the fluoro-3-of 2-(4-(cyclopentylcarbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(the fluoro-3-of 5-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(the fluoro-3-of 5-(4-(cyclopentylcarbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(the chloro-3-of 4-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(the chloro-3-of 4-(4-(cyclohexyl-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-((2-(4-(cyclopentylcarbonyl) piperazine-1-carbonyl) furans-5-base) methyl) quinazoline-2,4 (1H, 3H)-diketone;
1-((2-(4-(benzo [d] isothiazole-3-base) piperazine-1-carbonyl) furans-5-base) methyl) quinazoline-2,4 (1H, 3H)-diketone;
1-((2-(4-(cyclopentylcarbonyl) piperazine-1-carbonyl) pyridine-6-base) methyl) quinazoline-2,4 (1H, 3H)-diketone;
1-((2-(4-(pyridine-2-base) piperazine-1-carbonyl) pyridine-6-base) methyl) quinazoline-2,4 (1H, 3H)-diketone;
1-((2-(4-(pyrimidine-2-base) piperazine-1-carbonyl) pyridine-6-base) methyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(3-(4-(thiazol-2-yl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(3-(4-(cyclohexyl methyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(3-(4-(cyclopentyl-methyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(3-(4-(cyclohexylsulfonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 7-(3-(4-(cyclopentylcarbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 7-(3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
7-methyl isophthalic acid-(3-(4-(cyclopentylcarbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
7-methyl isophthalic acid-(3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
6-methyl isophthalic acid-(3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
6-methyl isophthalic acid-(3-(4-(cyclopentylcarbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
6-methyl isophthalic acid-(the fluoro-3-of 4-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
6-methyl isophthalic acid-(the fluoro-3-of 4-(4-(cyclohexyl-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
6-methyl isophthalic acid-(the fluoro-3-of 4-(4-(cyclopentylcarbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The bromo-1-of 6-(3-(4-(cyclohexyl-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The bromo-1-of 6-(3-(4-(cyclopentylcarbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The bromo-1-of 6-(3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
6-nitro-1-(3-(4-(cyclopentylcarbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
6-nitro-1-(3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
6-nitro-1-(3-(4-(cyclohexyl-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(4-(4-benzoyl piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(4-(4-(pyridine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(4-(4-(4-methoxybenzoyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(4-(4-(4-fluorobenzoyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(4-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(4-(4-(4-Bromophenacyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(4-(4-(cyclopentylcarbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The chloro-1-of 5-(3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The chloro-1-of 5-(3-(4-(cyclopentylcarbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The chloro-1-of 5-(3-(4-(cyclohexyl-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The chloro-1-of 5-(the fluoro-3-of 4-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The chloro-1-of 5-(the fluoro-3-of 4-(4-(cyclopentylcarbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The chloro-1-of 5-(the fluoro-3-of 4-(4-(cyclohexyl-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The chloro-1-of 5-(the fluoro-3-of 4-(4-(pyridine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The chloro-1-of 5-(the fluoro-3-of 4-(4-(thiophene-2-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The chloro-1-of 5-(the fluoro-3-of 6-(4-(cyclohexyl-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The chloro-1-of 5-(the fluoro-3-of 6-(4-(cyclopentylcarbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The chloro-1-of 5-(the fluoro-3-of 6-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The chloro-1-of 6-(3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The chloro-1-of 6-(3-(4-(cyclopentylcarbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The chloro-1-of 6-(3-(4-(cyclohexyl-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The chloro-1-of 6-(3-(4-(pyridine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The chloro-1-of 6-(3-(4-(thiophene-2-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The chloro-1-of 6-(3-(4-(cyclobutyl carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The chloro-1-of 6-(the fluoro-3-of 4-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The chloro-1-of 6-(the fluoro-3-of 4-(4-(cyclopentylcarbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The chloro-1-of 6-(the fluoro-3-of 4-(4-(cyclohexyl-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The chloro-1-of 6-(the fluoro-3-of 4-(4-(pyridine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The chloro-1-of 6-(the fluoro-3-of 4-(4-(thiophene-2-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The chloro-1-of 6-(the fluoro-3-of 4-(4-(cyclopropyl carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The chloro-1-of 6-(the fluoro-3-of 6-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The chloro-1-of 6-(the fluoro-3-of 6-(4-(cyclopentylcarbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The chloro-1-of 6-(the fluoro-3-of 6-(4-(cyclohexyl-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The chloro-1-of 6-(the fluoro-3-of 6-(4-(thiophene-2-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 5-(3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 5-(3-(4-(cyclopentylcarbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 5-(3-(4-(cyclohexyl-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 5-(3-(4-(pyridine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 5-(3-(4-(thiophene-2-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 5-(the fluoro-3-of 4-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 5-(the fluoro-3-of 4-(4-(cyclopentylcarbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 5-(the fluoro-3-of 4-(4-(cyclohexyl-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 5-(the fluoro-3-of 4-(4-(pyridine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 5-(the fluoro-3-of 4-(4-(thiophene-2-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 5-(the fluoro-3-of 4-(4-benzoyl piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 8-(3-(4-(cyclohexyl-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 6-(3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 6-(3-(4-(pyridine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 6-(3-(4-(thiophene-2-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 6-(3-(4-(cyclohexyl-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 6-(3-(4-(cyclopentylcarbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 6-(the fluoro-3-of 4-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 6-(the fluoro-3-of 4-(4-(pyridine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 6-(the fluoro-3-of 4-(4-(thiophene-2-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 6-(the fluoro-3-of 4-(4-(cyclohexyl-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 6-(the fluoro-3-of 4-(4-(cyclopentylcarbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 6-(the fluoro-3-of 6-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 6-(the fluoro-3-of 6-(4-(pyridine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 6-(the fluoro-3-of 6-(4-(thiophene-2-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 6-(the fluoro-3-of 6-(4-(cyclohexyl-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 6-(the fluoro-3-of 6-(4-(cyclopentylcarbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 5-(the fluoro-3-of 6-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 5-(the fluoro-3-of 6-(4-(pyridine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 5-(the fluoro-3-of 6-(4-(thiophene-2-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 5-(the fluoro-3-of 6-(4-(cyclohexyl-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 5-(the fluoro-3-of 6-(4-(cyclopentylcarbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
5-methyl isophthalic acid-(3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
5-methyl isophthalic acid-(3-(4-(cyclopentylcarbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The chloro-1-of 7-(3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The chloro-1-of 7-(3-(4-(cyclopentylcarbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 5-(the fluoro-3-of 4-(4-(cyclopropyl carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The chloro-1-of 6-(the fluoro-3-of 4-(4-benzoyl piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 5-(3-(4-(cyclobutyl carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 5-(the fluoro-3-of 4-(4-(cyclobutyl carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The chloro-1-of 6-(the fluoro-3-of 6-(4-(cyclobutyl carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The chloro-1-of 5-(the fluoro-3-of 4-(4-(cyclobutyl carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The chloro-1-of 6-(the fluoro-3-of 4-(4-(cyclobutyl carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The chloro-1-of 5-(the fluoro-3-of 6-(4-(cyclobutyl carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The chloro-1-of 5-(the fluoro-3-of 6-(4-(thiophene-2-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 5-(the fluoro-3-of 4-(4-(furans-2-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The chloro-1-of 5-(the fluoro-3-of 6-(4-(pyridine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The chloro-1-of 6-(the fluoro-3-of 6-(4-(pyridine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The chloro-1-of 6-(the fluoro-3-of 5-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 5-(the fluoro-3-of 5-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(3-(4-cyclopentyl-based piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 6-(the fluoro-3-of 4-(4-(cyclopropyl carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 6-(3-(4-(cyclobutyl carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 6-(the fluoro-3-of 4-(4-(cyclobutyl carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 6-(the fluoro-3-of 4-(4-benzoyl piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 5-(the fluoro-3-of 6-(4-(cyclobutyl carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 6-(the fluoro-3-of 6-(4-(cyclobutyl carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 5-(the fluoro-3-of 6-(4-(furans-2-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 6-(the fluoro-3-of 4-(4-(furans-2-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 6-(the fluoro-3-of 5-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 6-(the chloro-3-of 6-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 6-(the fluoro-3-of 4-(4-(thiazol-2-yl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 5-(the fluoro-3-of 4-(4-(thiazol-2-yl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(the fluoro-3-of 4-(4-(thiazol-2-yl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(3-(4-(cyclohexyl carboxyamide base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(the fluoro-3-of 4-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-dione hydrochloride;
The fluoro-1-of 5-(the fluoro-3-of 4-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-dione hydrochloride;
1-(3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-dione hydrochloride;
1-(3-((4-(pyridine-2-base) piperazine-1-base) methyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(3-(naphthalene-2-base) Acetamidobenzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(3-(3,4-Dimethoxyphenyl) Acetamidobenzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(3-([1,2,4] triazole [4,3-a] pyridine-6-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 6-((2-(4-(pyrimidine-2-base) piperazine-1-carbonyl) pyridine-6-base) methyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 5-(the fluoro-3-of 4-(4-methoxYbenzylamino formyl radical) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 5-(the fluoro-3-of 4-(3-chlorobenzylcarbamoyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 5-(the fluoro-3-of 4-(carbamovl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
5-methoxyl group-1-(3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
6-methoxyl group-1-(3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 5-(the fluoro-3-of 4-(5-bromo pyrimi piperidine-2-carbamoylamino) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
7-Trifluoromethyl-1-(3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
6,7-ethylene Oxy-1-(3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 5-(6-methoxyl group-3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
7-methoxyl group-1-(3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 5-(the fluoro-3-of 4-(4-(tetrahydrofuran (THF)-2-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 5-(4-nitro-3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 5-(the fluoro-3-of 4-(4-cyclohexylpiperazin-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 5-(the fluoro-3-of 4-(4-phenylpiperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 5-(the fluoro-3-of 4-(4-Phenylpiperidine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 5-(the bromo-3-of 4-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
6,7-methylenedioxy-1-(3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 5-(the fluoro-3-of 4-(4-(cyclohexyl methyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 8-(3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
6-amino-1-(3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(2-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The chloro-1-of 8-(3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
8-methyl isophthalic acid-(3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
8-methoxyl group-1-(3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
8-hydroxyl-1-(3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
Or its pharmacologically acceptable salt or prodrug.
" alkyl " used herein refers to alkyl itself or the straight or branched group up to ten carbon atoms.Useful alkyl comprises straight or branched C 1-10alkyl, preferred C 1-6alkyl.Typical C 1-10alkyl comprises methyl, ethyl, propyl group, sec.-propyl, butyl, sec-butyl, the tertiary butyl, 3-amyl group, hexyl and the octyl group that can be optionally substituted.
" alkenyl " used herein refers to that straight or branched contains 2-10 carbon atom, unless carbon chain lengths is limited in addition, is at least wherein the group containing a double bond between two carbon atoms in chain.Typical alkenyl comprises vinyl, 1-propenyl, 2-propenyl, 2-methyl-1-propylene base, 1-butylene base and crotyl.
" alkynyl " used herein refers to that straight or branched contains 2-10 carbon atom, unless carbon chain lengths is limited in addition, is at least wherein the group containing three key between two carbon atoms in chain.Typical alkynyl comprises ethynyl, 1-proyl, 1-methyl-2-propynyl, 2-propynyl, ethyl acetylene base and 2-butyne base.
Useful alkoxyl group comprises by above-mentioned C 1-10one of them oxygen base replaced of alkyl, the alkyl in alkoxyl group can be optionally substituted.The substituting group of alkoxyl group includes but not limited to that halogen, morpholinyl, amino comprise alkylamino and dialkylamino and carboxyl (comprising its ester group).
Useful alkylthio comprises by above-mentioned C 1-10one of them sulfenyl replaced of alkyl, the alkyl in alkylthio can be optionally substituted.Also comprise sulfoxide and the sulfone of this kind of alkylthio simultaneously.
Useful amino and the amino that can be optionally substituted comprise-NH 2,-NHR 15with-NR 15r 16, wherein R 15and R 16the C that can be optionally substituted 1-10alkyl, cycloalkyl, aryl, heteroaryl or amino.Or R 15and R 165-8 element heterocycle such as piperidines is formed together with N, or R 15and R 16with N and form 5-8 element heterocycle such as piperazine together with other N or O.Described alkyl and heterocycle can be optionally substituted.
Herein, when substituted, alkyl, alkoxyl group, alkylthio, alkenyl, alkynyl, cycloalkyl, carbonyl, carbocyclic ring and heterocycle, aryl, arylalkyl, aromatic yl alkenyl, aromatic yl polysulfide yl, heteroaryl and heteroarylalkyl can be selected from the substituting group replacement of following group by one or more (such as 1,2,3 or 4): halogen, hydroxyl, carboxyl, amino, nitro, cyano group, C 1-6amido, C 1-6acyloxy, C 1-6alkoxyl group, aryloxy, alkylthio, C 1-C 6alkyl, C 6-C 10aryl, C 3-C 8cycloalkyl, C 2-C 6alkenyl, C 2-C 6alkynyl, C 6-C 10aryl (C 2-C 6) alkenyl, C 6-C 10aryl (C 2-C 6) alkynyl, saturated and undersaturated heterocyclic radical or heteroaryl, methylenedioxy, C 1-C 6haloalkyl, C 6-C 10aryl (C 1-C 6) alkyl, C 1-C 6hydroxyalkyl, urea groups, sulfydryl, azido-, carbonyl, two (C 1-C 10alkyl) amino, alkane alkylsulfonyl, sulfamyl, dialkyl sulfamine and alkyl sulphinyl etc.Wherein substituting group itself also can be optionally substituted.
When substituted, alkyl, alkoxyl group, alkylthio, alkenyl, alkynyl, cycloalkyl, carbonyl, carbocyclic ring and heterocycle can be selected from the substituting group replacement of following group by one or more (such as 1,2,3 or 4): halogen, hydroxyl, carboxyl, amino, nitro, cyano group, C 1-6amido, C 1-6acyloxy, C 1-6alkoxyl group, aryloxy, alkylthio, C 6-C 10aryl, C 3-C 8cycloalkyl, C 2-C 6alkenyl, C 2-C 6alkynyl, C 6-C 10aryl (C 2-C 6) alkenyl, C 6-C 10aryl (C 2-C 6) alkynyl, saturated and undersaturated heterocyclic radical or heteroaryl.
When substituted, aryl, arylalkyl, aromatic yl alkenyl, aromatic yl polysulfide yl, heteroaryl and heteroarylalkyl can be selected from the substituting group replacement of following group by one or more (such as 1,2,3 or 4): halogen, methylenedioxy, C 1-C 6haloalkyl, C 6-C 10aryl, C 3-C 8cycloalkyl, C 1-C 6alkyl, C 2-C 6alkenyl, C 2-C 6alkynyl, C 6-C 10aryl (C 1-C 6) alkyl, C 6-C 10aryl (C 2-C 6) alkenyl, C 6-C 10aryl (C 2-C 6) alkynyl, C 1-C 6hydroxyalkyl, nitro, amino, urea groups, cyano group, C 1-C 6acyl group amido, hydroxyl, sulfydryl, C 1-C 6acyloxy, azido-, C 1-C 6alkoxyl group, carbonyl, carboxyl, two (C 1-C 10alkyl) amido, alkyl sulphonyl, amino-sulfonyl, dialkyl amino alkylsulfonyl or alkyl sulphinyl.
" aryl " used herein refers to aryl itself or the part as other group, refers to the monocycle containing 6 to 14 carbon atoms, dicyclo or three cyclic aromatic groups.
Useful aryl comprises C 6-14aryl, preferably C 6-10aryl.Typical C 6-14aryl comprises phenyl, naphthyl, phenanthryl, anthryl, indenyl, Azulene base, xenyl, biphenylene and Fluorene base.
Here indication " carbocyclic ring " comprises the carbon ring group of cycloalkyl and fractional saturation.Useful cycloalkyl is C 3-8cycloalkyl.Typical cycloalkyl comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and suberyl.
The carbon ring group of useful saturated or fractional saturation is cycloalkyl described above and cycloalkenyl group, such as cyclopentenyl, cycloheptenyl and cyclooctene base.
Useful halogen or halogen group comprise fluorine, chlorine, bromine and iodine.
" arylalkyl " used herein comprises by arbitrary above-mentioned C 6-14the C that aryl replaces 1-10alkyl.Preferred arylalkyl is benzyl, styroyl or menaphthyl.
" aromatic yl alkenyl " used herein comprises by arbitrary above-mentioned C 6-14the C that aryl replaces 2-10alkenyl.
" aromatic yl polysulfide yl " used herein comprises by arbitrary above-mentioned C 6-14the C that aryl replaces 2-10alkynyl.
" aryloxy " used herein comprises by arbitrary above-mentioned C 6-14the oxygen base that aryl replaces, its aryl can be optionally substituted.Useful aryloxy comprises phenoxy group and 4-methylphenoxy.
" alkoxy aryl " used herein comprises the C replaced by arbitrary above-mentioned aryl 1-10alkoxyl group, its aryl can be optionally substituted.Useful alkoxy aryl comprises benzyloxy and phenyl ethoxy.
Useful haloalkyl comprises the C replaced by one or more fluorine, chlorine, bromine or iodine atom 1-10alkyl, preferably C 1-C 6alkyl, such as methyl fluoride, difluoromethyl, trifluoromethyl, pentafluoroethyl group, 1,1-bis-fluoro ethyl, chloromethyl, chlorine methyl fluoride and trichloromethyl.
Useful acyl group amido (amide group) is any C be connected on amido nitrogen 1-6acyl group (alkyloyl), such as acetamido, chloracetyl amido, propionamido-, amide-based small, valeryl amido and hexanoyl amido, and the C that aryl replaces 1-6acyl group amido, such as benzoylamino and penta fluoro benzene formamido-.Useful acyl group comprises C 1-6acyl group, as ethanoyl.
Useful acyloxy is any C be connected on oxygen (-O-) 1-6acyl group (alkyloyl), such as methanoyl, acetoxyl group, propionyloxy, butyryl acyloxy, penta acyloxy and hexylyloxy.
Heterocycle used herein (heterocyclic radical) refers to 3-7 person's monocycle that is saturated or fractional saturation, or 7-10 person's bicyclic system, it by carbon atom and from O, N, S optional 1-4 heteroatoms form, wherein heteroatoms nitrogen and sulphur can be oxidized arbitrarily, nitrogen also can be quaternary ammoniated arbitrarily, and comprise the fusion of any heterocycle defined above and phenyl ring in bicyclic system.If the compound produced is stable, so the carbon atom of heterocycle or nitrogen-atoms can be substituted.
Useful saturated or fractional saturation heterocyclic group comprises tetrahydrofuran base, pyranyl, piperidyl, piperazinyl, pyrrolidyl, imidazolidyl, imidazolinyl, indolinyl, iso-dihydro-indole-group, quinuclidinyl, morpholinyl, different chromanyl, chromanyl, pyrazolidyl, pyrazolinyl, tetronoyl and tetramoyl, and these groups can be optionally substituted.
" hetero-aromatic ring " used herein refers to containing 5-14 annular atoms, and has 6, and 10 or 14 π-electrons share in member ring systems.And contained annular atoms is carbon atom and 1-3 optional from oxygen, nitrogen, a sulphur heteroatoms.
Useful heteroaryl comprises thienyl (thiophenyl), benzo [d] isothiazole-3-base, benzo [b] thienyl, naphtho-[2,3-b] thienyl, thianthrenyl, furyl, pyranyl, isobenzofuran-base, chromenyl, xanthyl, thiophene dislikes base (phenoxanthiinyl), pyrryl, imidazolyl, pyrazolyl, pyridyl, include, but are not limited to 2-pyridyl, 3-pyridyl and 4-pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, indolizine base, pseudoindoyl, 3H-indyl, indyl, indazolyl, purine radicals, 4H-quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinazolyl, cinnolines base, pteridyl, carbazyl, β-carboline base, phenanthridinyl, acridyl, naphthalene embedding phenodiazine (mixing) phenyl, phenanthroline base, phenazinyl, isothiazolyl, phenothiazinyl, isoxazolyl, furazan base, Phenazoxine base, Isosorbide-5-Nitrae-dihydro-quinoxaline-2,3-diketone, the amino Isocoumarin of 7-, pyrido [1,2-a] pyrimidin-4-one, tetrahydro-five member [c] pyrazole-3-yls, pyrazoles [1,5-a] pyrimidyl, benzisoxa oxazolyl is as 1,2-benzisoxa oxazole-3-base, benzimidazolyl-, 2-oxindole base, thiadiazole base and 2-oxobenzimidazolyl.When heteroaryl contains nitrogen-atoms in ring, such nitrogen-atoms can be N-oxide form, such as pyridyl N-oxide, pyrazinyl N-oxide compound and pyrimidinyl N-oxide.
" heteroaryloxy " used herein comprises the oxygen base replaced by arbitrary above-mentioned heteroaryl, wherein heteroaryl can have substituting group.Useful heteroaryloxy comprises pyridyloxy, pyrazine oxygen base, pyrroles's oxygen base, pyrazoles oxygen base, imidazoles oxygen base and thiophenyl oxygen base.
" heteroarylalkoxy " used herein refers to the arbitrary above-mentioned C replaced by arbitrary above-mentioned heteroaryl 1-10alkoxyl group, wherein heteroaryl can have substituting group.
Some the compounds of this invention as steric isomer, may comprise optically active isomer and exist.The present invention includes the racemic mixture of all steric isomers and such steric isomer, and the independent enantiomorph can separated according to method well known to the skilled person.
The example of pharmacologically acceptable salt comprises inorganic and organic acid salt, such as hydrochloride, hydrobromate, phosphoric acid salt, vitriol, Citrate trianion, lactic acid salt, tartrate, maleate, fumarate, mandelate and oxalate; And the inorganic and organic alkali salt to be formed with alkali such as sodium hydroxyl, three (hydroxymethyl) aminomethane (TRIS, amine trihydroxybutane) and N-METHYL-ALPHA-L-GLUCOSAMINE.
The embodiment of the prodrug of the compounds of this invention comprise the compound containing carboxylic acid simple ester (such as according to means known in the art by with C 1-4alcohol condensation and the ester obtained); The ester of the compound containing hydroxyl (such as according to means known in the art by with C 1-4carboxylic acid, C 3-6diacid or its acid anhydrides such as succinyl oxide and fumaric acid anhydride condensation and the ester obtained); Imines containing amino compound (such as according to means known in the art by with C 1-4aldehydes or ketones condensation and the imines obtained); Carbamate containing amino compound, those esters that the people (J.Med.Chem.42:3657-3667 (1999)) such as the people such as such as Leu (J.Med.Chem.42:3623-3628 (1999)) and Greenwald describe; The acetal of the compound containing alcohol or ketone acetal (such as according to means known in the art by with Chloromethyl methyl ether or chloromethyl ethyl ether condensation and those acetals of obtaining).
The compounds of this invention can use method known to those skilled in the art or novel method of the present invention to obtain.Specifically, have formula I, the compounds of this invention of formula II or formula III can obtain (Shunsuke Goto et al.Organic Process Research & Development, 2003 as shown in the reaction embodiment in reaction scheme 1,7,700-706).Quinazoline-2,4 (1H, 3H)-diketone and hexamethyldisilazane (HMDS) back flow reaction in toluene and the vitriol oil obtain intermediate product 2,4-bis-(trimethylsiloxy group) quinazoline.2,4-bis-(trimethylsiloxy group) quinazoline and replacement 3-halogenated methyl phenylformic acid alkyl ester are if 3-bromomethyl-benzoic acid methyl ester is at DMF, then react in dioxane and methyl alcohol, obtain product 1-(3-methoxycarbonyl benzyl) quinazoline-2,4 (1H, 3H)-diketone.This ester is at sodium hydroxide, and in water and methyl alcohol, back flow reaction hydrolysis, obtains product 1-(3-carboxybenzyl) quinazoline-2,4 (1H, 3H)-diketone.This acid and replacement ammonia such as 1-(pyridine-2-base) piperazine, and condensing agent is as 2-(7-azo benzotriazole)-N, N, N', N'-tetramethyl-urea phosphofluoric acid ester (HATU) and DIPEA (DIPEA) react in DMF, obtain target product 1-(3-(4-(pyridine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone.
Other related compound can obtain by similar approach.Such as, substitute 3-(brooethyl) methyl benzoate with 6-(brooethyl) pyridine-2-methyl-formiate and can obtain target compound 1-((2-(4-(pyridine-2-base) piperazine-1-carbonyl) pyridine-6-base) methyl) quinazoline-2,4 (1H, 3H)-diketone.Substitute 3-(brooethyl) methyl benzoate with 5-(chloromethyl) furans-2-methyl-formiate and can obtain target compound 1-((2-(4-cyclopentylcarbonyl piperazine-1-carbonyl) furans-5-base) methyl) quinazoline-2,4 (1H, 3H)-diketone.Substitute 3-(brooethyl) methyl benzoate with 3-(2-bromotrifluoromethane) methyl benzoate and can obtain target compound 1-(3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) styroyl) quinazoline-2,4 (1H, 3H)-diketone.
For the quinazoline-2 of 8 substds, 4 (1H, 3H)-diketone, as 8-chloro-quinazoline-2,4 (1H, 3H)-diketone, react with hexamethyldisilazane (HMDS), the intermediate 8-chloro-2 obtained, 4-bis-(trimethylsiloxy group) quinazoline and 3-(brooethyl) methyl benzoate react and can obtain 1-(3-methoxycarbonyl benzyl) quinazoline-2,4 (1H, 3H)-diketone and 3-(3-methoxycarbonyl benzyl) quinazoline-2, the mixture of 4 (1H, 3H)-diketone.This mixture is separable, hydrolysis, obtains 1-respectively replace and 3-substitution compound with the coupling of replacement amine.In addition, quinazoline-2,4 (1H, 3H)-diketone and 3-(brooethyl) methyl benzoate are at K 2cO 3and 3-(methoxycarbonyl benzyl) quinazoline-2,4 (1H, 3H)-diketone can be obtained under DMF condition, then through being hydrolyzed the acid that obtains and replacing amine and react and also can obtain 3-substitution compound.
The compounds of this invention can obtain as shown in the reaction embodiment in reaction scheme 2.2,4-bis-(trimethylsiloxy group) quinazoline and replacement 3-halogenated methyl phenylformic acid alkyl ester are if 5-brooethyl-2-fluorophenyl carbamate is at DMF, then react in dioxane and methyl alcohol, obtain product 1-(the fluoro-3-methoxycarbonyl benzyl of 4-) quinazoline-2,4 (1H, 3H)-diketone.This ester is at sodium hydroxide, and in water and methyl alcohol, back flow reaction hydrolysis, obtains product 1-(the fluoro-3-carboxybenzyl of 4-) quinazoline-2,4 (1H, 3H)-diketone.This acid and replacement ammonia such as 1-cyclopentylcarbonyl piperazine, and condensing agent such as HATU and DIPEA reacts in DMF, obtain target product 1-(the fluoro-3-of 4-(4-cyclopentylcarbonyl piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone.
Other related compound can obtain by similar approach.Such as, with the quinazoline-2 replaced, 4 (1H, 3H)-diketone is as 5-fluquinconazole quinoline-2,4 (1H, 3H)-diketone (with 2-amino-6-fluorobenzoic acid and potassium cyanate Reactive Synthesis) substitutes quinazoline-2,4 (1H, 3H)-diketone, can obtain the fluoro-1-of target compound 5-(the fluoro-3-of 4-(4-cyclopentylcarbonyl piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone.5-brooethyl-2-fluorophenyl carbamate is substituted with 3-(brooethyl) methyl benzoate such as 3-(the brooethyl)-4-fluorophenyl carbamate that other replaces, target compound 1-(the fluoro-3-of 6-(4-cyclopentylcarbonyl piperazine-1-carbonyl) benzyl) quinazoline-2 can be obtained, 4 (1H, 3H)-diketone.1-cyclopentylcarbonyl piperazine is substituted with other replacement amine such as 1-(pyrimidine-2-base) piperazine, target compound 1-(the fluoro-3-of 4-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2 can be obtained, 4 (1H, 3H)-diketone.
The compounds of this invention can obtain as shown in the reaction embodiment in reaction scheme 3.2-amino-3-tolyl acid and triphosgene are obtained by reacting 8-methyl isophthalic acid H-benzo [d] [1,3] oxazines-2,4-diketone in THF.8-methyl isophthalic acid H-benzo [d] [1,3] oxazines-2,4-diketone and TERTIARY BUTYL AMINE and DMAP are obtained by reacting 2-Amino-N-tert-butyl-3-methyl benzamide in DMF.This benzamide and CDI are obtained by reacting the 3-tertiary butyl-8-methylquinazolin-2,4 (1H, 3H)-diketone in THF.This diketone and 3-(brooethyl) methyl benzoate and MeONa react in DMF, then add aqueous hydrochloric acid and are obtained by reacting 8-methyl isophthalic acid-(3-carboxybenzyl) quinazoline-2,4 (1H, 3H)-diketone.This acid and 2-(piperazine-1-base) pyrimidine and coupling reagent such as HATU and DIPEA are obtained by reacting target compound 8-methyl isophthalic acid-(3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2 in DMF, 4 (1H, 3H)-diketone.
Other related compound can be obtained by similar approach.Such as, replace 2-benzaminic acid such as 2-amino-3-methoxybenzoic acid with other and substitute 2-amino-3-tolyl acid, target compound 8-methoxyl group-1-(3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2 can be obtained, 4 (1H, 3H)-diketone.
1-phenyl compound can obtain as shown in the reaction embodiment in reaction scheme 4.2-bromaniline and oxalyl chloride react in DCM, then add 3-Methyl anthranilate and are obtained by reacting 3-(3-(2-Bromophenacyl) urea groups) methyl benzoate.3-(3-(2-Bromophenacyl) urea groups) methyl benzoate and potassium tert.-butoxide are obtained by reacting 1-(3-methoxycarbonyl-phenyl) quinazoline-2,4 (1H, 3H)-diketone in DMF.This ester and NaOH are obtained by reacting 1-(3-carboxyl phenyl) quinazoline-2,4 (1H, 3H)-diketone in water-methanol solution.This acid and 2-(piperazine-1-base) pyrimidine and coupling reagent such as HATU and DIPEA are obtained by reacting target compound 1-(3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) phenyl) quinazoline-2 in DMF, 4 (1H, 3H)-diketone.
An importance of the present invention has found formula I, and the compound of formula II and formula III is PARP inhibitor.Therefore, these compounds can be used for treating the multiple clinical disease caused because PARP is extremely active, such as cancer.
The present invention also comprises the formula I using significant quantity to animal, the methods for the treatment of of formula II or formula III compound or pharmaceutically acceptable salt thereof or prodrug.Wherein said methods for the treatment of is used for the treatment of the various illnesss caused because PARP is extremely active, such as cancer.Liver cancer can be included but not limited to by this kind of disease of method of the present invention or medicine composite for curing or prevention, melanoma, Hodgkin's disease, non-Hodgkin lymphoma, acute lymphatic leukaemia, chronic lymphocytic leukemia, multiple myeloma, neuroblastoma, mammary cancer, ovarian cancer, lung cancer, wilms' tumor, cervical cancer, carcinoma of testis, soft tissue sarcoma, primary macroglobulinaemia, wing indulges in cancer, chronic myelocytic leukemia, primary brain cancer, malignant melanoma, small cell lung cancer, cancer of the stomach, colorectal carcinoma, malignant pancreatic insulinoma, malignant carcinoid carcinomas, choriocarcinoma, gill fungus Sample Rou Ya Swollen, head or neck cancer, osteogenic sarcoma, carcinoma of the pancreas, acute myeloblastic leukemia, hairy cell leukemia, rhabdosarcoma, Kaposi sarcoma, urogenital neoplasm is sick, thyroid carcinoma, the esophageal carcinoma, malignant hypercalcemia, hyperplasia of cervix uteri disease, renal cell carcinoma, carcinoma of endometrium, polycythemia vera, essential thrombocythemia, adrenocortical carcinoma, skin carcinoma and prostate cancer.
The present invention also comprises the other diseases being used for the treatment of or preventing to cause because PARP is extremely active, and such as excessive necrocytosis, comprises the central nervous system disease such as apoplexy and nerve degenerative diseases.
When implementing subject treatment method, to the pharmaceutical preparation having the patient of one or more these symptoms to use significant quantity.Described pharmaceutical preparation contains the formula I of effectively treatment concentration, formula II or formula III compound, is formulated for the form of oral, intravenous injection, local or topical administration, is used for the treatment of cancer and other diseases.Dosage effectively improves or eliminate the dose of one or more illness.For the treatment of specified disease, significant quantity is the dose being enough to improve or alleviate in some manner the symptom relevant with disease.Such dose can be used as single dose and uses, or can according to effective treatment plan administration.Dosage also permits cure diseases, but administration is normally in order to improve the symptom of disease.Repetitively administered is generally needed to improve to realize required symptom.
Provide a kind of medicinal compositions in another embodiment, wherein containing the formula I of PARP inhibitor, formula II or formula III compound or pharmaceutically acceptable salt thereof and pharmaceutically acceptable carrier.
Another embodiment of the invention relates to can the medicinal compositions of Therapeutic cancer effectively, wherein comprise the formula I of PARP inhibitor, formula II or formula III compound, or its pharmacologically acceptable salt or prodrug, the cancer therapy drug known with at least one or the pharmacologically acceptable salt of cancer therapy drug are combined shared.The known anticancer drugs that can be used for anti-cancer combination treatment includes but not limited to alkylating agent such as busulfan, melphalan, Chlorambucil, endoxan, ifosfamide, Temozolomide, bendamustine, cis-platinum, ametycin, bleomycin and carboplatin; Topoisomerase I inhibitor is camptothecine, irinotecan and Hycamtin such as; Topoisomerase II inhibitors such as Zorubicin, pidorubicin, aclacinomycin, mitoxantrone, NSC-264137 and inscription holder pool is general; RNA/DNA metabolic antagonist such as 5-azepine born of the same parents are general, gemcitabine, 5-fluorine urine is crowed to suck and chanted with first atmosphere butterfly; The fluoro-2'-uracil deoxyriboside of DNA metabolic antagonist such as 5-, fludarabine, Nelzarabine, cytosine arabinoside, the cry of certain animals of sulphur bird throat, Pralatrexate, pemetrexed, hydroxyurea and thioguanine; Antimitotic agent is colchicine, vinealeucoblastine(VLB), vincristine(VCR), vinorelbine, taxol, ipsapirone, Cabazitaxel and docetaxel such as; Antibody is monoclonal antibody (campath), Victibix, Ofatumumab, Avastin, Trastuzumab and Mabthera such as; Kinase inhibitor such as imatinib, Gefitinib, erlotinib, lapatinibditosylate, Xarelto, Sutent, nilotinib, Dasatinib, pazopanib, special cancer accommodate everolimus; Hdac inhibitor such as Vorinostat and sieve miaow ester peptide.Other known anticancer drugs that can be used for anti-cancer combination treatment comprise tamoxifen, letrozole, fulvestrant, mitoguazone, Sostatin, vitamin A acid, arsenic, Zoledronic acid, Velcade, Sa Li polyamines and Revlimid.
When implementing method of the present invention, the cancer therapy drug that the compounds of this invention is known with at least one can be used as administration together with single medicinal compositions.In addition, the compounds of this invention also can separate administration with the known anticarcinogen of at least one.An embodiment, the compounds of this invention and the similar administration simultaneously of the known anticarcinogen of at least one, namely all medicines are used simultaneously or are used successively, as long as compound reaches treatment concentration in blood simultaneously.In another one embodiment, compound of the present invention and the known anticarcinogen of at least one are according to respective dose regimen, as long as compound reaches treatment concentration in blood.
Another embodiment of the invention is a kind of by described compound, as the biological coupling thing of the effective Tumor suppression of energy of PARP inhibitor composition.This can the biological coupling thing of Tumor suppression by described compound and the known antibody having medical functions of at least one, as Trastuzumab or Mabthera, or growth hormone, as DGF or NGF, or cytohormone, as interleukin II or 4, or the molecular composition that can be combined with cell surface arbitrarily.This antibody and other molecular energies to its target spot, make it described compound delivery become effective cancer therapy drug.This biological coupling thing also can improve the antibody having medical functions, as the anticancer effect of Trastuzumab or Mabthera.
Another embodiment of the present invention relates to the medicinal compositions of the effective Tumor suppression of a kind of energy, comprises the formula I of PARP inhibitor, formula II or formula III compound, or it can medication salt or prodrug, with radiotherapy combination therapy.In this embodiment, the compounds of this invention and radiotherapy can in same time or different time administrations.
Another embodiment of the present invention relate to a kind of can medicinal compositions effectively for treating after cancer operation, comprise the formula I of PARP inhibitor, formula II or formula III, or it can medication salt or prodrug.The invention still further relates to by ocal resection, then treat the methods for the treatment of of this mammiferous cancer with medicinal compositions of the present invention.
The amount that medicinal compositions of the present invention comprises all the compounds of this invention can realize the medicine preparation of its re-set target effectively.Although each Man's Demands is different, those skilled in the art can determine the optimal dose of each part in medicine preparation.Generally, described compound, or it can medication salt, and to Mammals oral administration every day, dose is according to about 0.0025 to 50 mgs/kg of body weight.But preferably per kilogram oral administration about 0.01 to 10 mgs/kg.If also use a known cancer therapy drug, its dosage should realize the object of its expection effectively.The optimal dose of these known cancer therapy drugs is well-known to those skilled in the art.
Unit oral doses can comprise about 0.01 to 50 milligrams, preferably the compounds of this invention of about 0.1 to 10 milligrams.Unitary dose can give one or many, and every day is one or more pieces, every sheet containing having an appointment 0.1 to 50 milligrams, the eligibly the compounds of this invention of about 0.25 to 10 milligrams or its solvate.
In external preparation, the concentration of the compounds of this invention can be about 0.01 to 100 milligrams, every gram of carrier.
The compounds of this invention can be used as undressed drug products for administration.The compounds of this invention also can be suitable as containing pharmaceutically acceptable carrier (comprising auxiliary material and auxiliary agent) a part of administration of pharmaceutical preparation.These pharmaceutically acceptable carrier are conducive to compound to be processed into pharmaceutically useful pharmaceutical preparation.Preferred pharmaceutical preparation, particularly those are oral with preferred administering mode type, as tablet, lozenge and capsule, and are suitable for injecting or oral solution, comprise about 0.01% to 99%, preferably from about 0.25% to 75% active compound and auxiliary material.
Scope of the present invention also comprises the nontoxicity pharmacologically acceptable salt of the compounds of this invention.Acid salt is by mixing a nontoxicity pharmaceutically acceptable acid solution and compound solution of the present invention and being formed.Described acid is hydrochloric acid, fumaric acid, toxilic acid, succsinic acid, acetic acid, citric acid, tartrate, carbonic acid, phosphoric acid, oxalic acid etc. such as.Base addition salt is by mixing a pharmaceutically acceptable alkaline solution of nontoxicity and compound solution of the present invention and being formed.Described alkali is sodium hydroxide, potassium hydroxide, hydrogen choline, sodium carbonate, Tutofusin tris, N-methyl glucose osamine etc. such as.
Pharmaceutical preparation of the present invention can give any Mammals, as long as they can obtain the result for the treatment of of the compounds of this invention.The most importantly mankind and veterinary animal in these Mammalss, although the present invention does not intend so limited.
Pharmaceutical preparation of the present invention by any administration with reach its expection object.Such as, can, encephalic, nasal cavity interior by intestines outer, subcutaneous, vein, muscle, intraperitoneal, transdermal, oral cavity, sheath or topical route administration.As an alternative or concurrently, oral administration can be passed through.Age according to patient, health and body weight, the kind of concurrent treatment, the frequency for the treatment of and required treatment benefit decide by the dosage of medicine.
Pharmaceutical preparation of the present invention can manufacture in a known manner.Such as, by traditional mixing, granulation, ingot processed, dissolving or freezing dry process manufacture.When manufacturing oral preparations, can in conjunction with solid adjuvant material and active compound, selectivity grinding mixture.If to need or after adding appropriate amount of addition agent if desired, processing granular mixture, obtains tablet or lozenge core.
Suitable auxiliary material particularly filler, such as carbohydrate is as lactose or sucrose, N.F,USP MANNITOL or sorbyl alcohol; Cellulose preparation and/or calcium phosphate, such as tricalcium phosphate or secondary calcium phosphate; And binding agent, such as starch paste, comprise W-Gum, wheat starch, Starch rice, yam starch, gelatin, tragacanth, methylcellulose gum, Vltra tears, Xylo-Mucine and/or polyvinylpyrrolidone.If needed, can disintegrating agent be increased, than starch as mentioned above, and carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar or alginic acid or its salt, as sodium alginate.Auxiliary is flowing regulator and lubricant particularly, and such as, silica, talcum, stearic acid or its salt, as Magnesium Stearate or calcium stearate and/or polyoxyethylene glycol.If needed, provide the suitable dressing can resisting gastric juice can to lozenge core core.For this reason, concentrated saccharide solution can be applied.This solution can contain Sudan Gum-arabic, talcum, polyvinylpyrrolidone, polyoxyethylene glycol and/or titanium dioxide, paint solution and suitable organic solvent or solvent mixture.In order to prepare the dressing of resistant to gastric juice, suitable cellulose solution can be used, such as cellulose acetate phthalic acid or Vltra tears phthalic acid.Dyestuff or pigment can be added to the dressing of tablet or lozenge core core.Such as, the combination for identifying or in order to characterize activeconstituents dosage.
Other can comprise the compression joint type capsule that gelatin makes by oral pharmaceutical preparation, and with the sealing soft capsule that gelatin and the softening agent such as glycerine or sorbyl alcohol are made.This compression joint type capsule can contain the active compound of particle form, with filler such as lactose; Binding agent is starch such as; And/or lubricant such as talcum powder or Magnesium Stearate, and stablizer mixes.At soft capsule, active compound is preferably dissolved or suspended in suitable liquid such as grease or whiteruss, wherein can add stablizer.
The preparation being appropriate to intestines external administration comprises the aqueous solution of active compound, as solution and the basic solution of water-soluble salt.In addition, the oily injection suspensions of suitable active compound can be used.Suitable lipophilic solvent or carrier comprise grease such as sesame oil, and Acrawax is ethyl oleate such as, or triglyceride level, or poly(oxyethylene glycol) 400, or hydrogenated castor oil, or cyclodextrin.Water injection suspension liquid can containing the material increasing suspension viscosity, such as Xylo-Mucine, sorbyl alcohol and/or dextran.Also suspension stabilizer can be contained.
According to one aspect of the present invention, compound of the present invention adopts external application and intestines to fill a prescription outward, and is used for the treatment of skin carcinoma.
External preparation of the present invention makes finish, creme, emulsion agent, ointment etc. by preferably suitable carrier.Suitable carrier comprises plant or mineral oil, white mineral oil (paraffinum molle alba), Branched fatty or grease, animal tallow and high molecular alcohol (are greater than C 12).Preferred carrier is those carriers that activeconstituents can be dissolved in wherein.Also can comprise emulsifying agent, stablizer, wetting Agent for Printing Inks and antioxidant, and if necessary, give the reagent of color or fragrance.In addition, these external preparations can comprise dermal penetration enhancers.The example of this toughener can see U.S. Patent number 3,989,816 and 4, and 444,762.
Creme is preferably prepared with the mixture of mineral oil, self emulsifying beeswax and water, mixes with the activeconstituents being dissolved in a small amount of oil such as Prunus amygdalus oil.A typical creme example comprises about 40 parts of water, 20 portions of beeswaxs, 40 parts of mineral oil and 1 portion of Prunus amygdalus oil.
Ointment can be prepared like this, by the vegetable oil containing activeconstituents as Prunus amygdalus oil and the mixing of warm soft wax, then makes this mixture cool.A typical ointment example comprises the Prunus amygdalus oil of about 30% weight and the paraffinum molle alba of 70% weight.
The present invention also relates to apply compound of the present invention preparation treatment to the medicine suppressing the active effective clinical disease of PARP.These medicines can comprise above-mentioned medicinal compositions.
The following example illustrates, instead of limit method and formulation of the present invention.Other will become apparent to those skilled in the art that and the suitable amendment to various condition and parameter that usually can run in clinical treatment and improvement, all within the spirit and scope of the present invention.
Embodiment
General explanation
Agents useful for same is all commercial qualities.Solvent is all according to the dry purifying of standard method.Single level Four bar mass spectrograph of analytical data of mass spectrum electron spray(ES) measures (platform II, Agilent 6110).Hydrogen spectrum is measured by Br ü cker AMX300 million nuclear magnetic resonance spectrometer under temperature 300K.Chemical shift is recorded as to be begun in units of ppm using TMS as interior mark (0.00ppm) from low field, and coupling constant J value is in units of hertz.
Embodiment 1
1-(3-methoxycarbonyl benzyl) quinazoline-2,4 (1H, 3H)-diketone
By quinazoline-2,4 (1H, 3H)-diketone (1.0g, 6.2mmol), hexamethyldisilazane (HMDS; 2.5g, 15.4mmol) and toluene 50mL join in 100mL bis-mouthfuls of bottles, add vitriol oil 0.06g under stirring, back flow reaction 8 hours.Underpressure distillation removing toluene and excessive HMDS, obtain intermediate product 2,4-bis-(trimethylsiloxy group) quinazoline.
In 50mL single port bottle, add intermediate product 2,4-bis-(trimethylsiloxy group) quinazoline, 3-bromomethyl-benzoic acid methyl ester (2.1g, 9.2mmol) and DMF (1mL) successively, be warming up to 115-130 DEG C of reaction 3 hours.Add dioxane (6mL) and methyl alcohol (10mL) after being cooled to 100 DEG C, reflux 30 minutes.After being cooled to room temperature, filter.Filter cake uses water (20mL) and methyl alcohol (10mL) washing respectively, dries, obtains desired product as white solid (1.6g, 83.7%). 1H?NMR(DMSO-d 6):11.76(s,1H),8.00(dd,J＝7.8,1.2Hz,1H),7.89(s,1H),7.83(d,J＝7.8Hz,1H),7.65-7.43(m,3H),7.25-7.20(m,2H),5.36(s,2H),3.80(s,3H)。MS:m/z311.1[M+H] +。
Embodiment 2
1-(3-carboxybenzyl) quinazoline-2,4 (1H, 3H)-diketone
1-(3-methoxycarbonyl benzyl) quinazoline-2 is added in 250mL there-necked flask, 4 (1H, 3H)-diketone (1.6g, 5.2mmol), sodium hydroxide (0.31g, 7.7mmol), water (40mL) and methyl alcohol (40mL), back flow reaction 3 hours.After reaction terminates, underpressure distillation removing methyl alcohol, has a large amount of solids to separate out with 3N aqueous hydrochloric acid adjust pH to 2-3.Filter, filter cake water and methanol wash, dry to obtain desired product as white solid (1.2g, 78%). 1H?NMR(DMSO-d 6):13.09(brs,1H),11.77(s,1H),8.01(dd,J＝7.7,1.4Hz,1H),7.84-7.80(m,2H),7.66-7.61(m,1H),7.53(d,J＝7.8Hz,1H),7.44(t,J＝7.7Hz,1H),7.27-7.21(m,2H),5.36(s,2H)。MS:m/z297.1[M+H] +。
Embodiment 3
1-(3-(4-(pyridine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
Compound 1-(3-carboxybenzyl) quinazoline-2 is added in 50mL two-mouth bottle, 4 (1H, 3H)-diketone (0.2mmol), 1-(pyridine-2-base) piperazine (0.2mmol), 2-(7-azepine-1H-benzotriazole-1-base)-1,1,3,3-tetramethyl-urea phosphofluoric acid ester (HATU, 0.26mmol), N, N-diisopropylethylamine (DIPEA, 0.4mmol) with DMF (5mL), stirring at room temperature 3 hours.Add water 50mL, extract with methylene dichloride (50mL × 2).Organic layer 1N aqueous hydrochloric acid (50mL × 2) washing, then use saturated brine (50mL × 2) to wash, anhydrous sodium sulfate drying, concentrating under reduced pressure obtains crude product.Desired product as white solid (7.7mg, 8.6%) is obtained through column chromatography (ethyl acetate). 1H?NMR(DMSO-d 6):11.69(s,1H),8.09(dd,J＝5.0,1.7Hz,1H),7.99(dd,J＝8.0,1.7Hz,1H),7.64(t,J＝7.1Hz,1H),7.53(t,J＝7.8Hz,1H),7.40-7.21(m,6H),6.77(d,J＝8.7Hz,1H),6.64(dd,J＝7.1,5.0Hz,1H),5.34(s,2H),3.40-3.20(m,8H)。MS:m/z442.3[M+H] +。
The synthetic method that following compound application class is similar to described embodiment 3 obtains, and starting raw material is 1-(3-carboxybenzyl) quinazoline-2,4 (1H, 3H)-diketone and corresponding substituted-piperazinyl or piperidines.
Embodiment 4
1-(3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
White solid. 1H?NMR(DMSO-d 6):11.71(s,1H),8.36(d,J＝4.8Hz,2H),8.01(d,J＝6.9Hz,1H),7.67-7.61(m,1H),7.42-7.24(m,6H),6.65(t,J＝4.8Hz,1H),5.35(s,2H),3.40-3.20(m,8H)。MS:m/z443.3[M+H] +。
Embodiment 5
1-(3-(4-cyclohexylpiperazin-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
White solid. 1H?NMR(DMSO-d 6):11.74(s,1H),8.00(d,J＝7.8Hz,1H),7.62(t,J＝7.5Hz,1H),7.43-7.38(m,2H),7.26-7.20(m,4H),5.33(s,2H),3.40-3.20(m,4H),2.21-2.15(m,4H),1.96-1.70(m,5H),1.21-1.08(m,6H)。MS:m/z447.3[M+H] +。
Embodiment 6
1-(3-(4-([1,2,4] triazolo [4,3-b] pyridazine-6-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
White solid. 1H?NMR(DMSO-d 6):11.73(s,1H),9.24(s,1H),8.12(d,J＝10.2Hz,1H),8.02(d,J＝7.8Hz,1H),7.66(t,J＝6.9Hz,1H),7.42-7.24(m,7H),5.36(s,2H),3.40-3.20(m,8H)。MS:m/z483.3[M+H] +。
Embodiment 7
1-(3-(4-ethyl piperazidine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
White solid. 1H?NMR(DMSO-d 6):11.72(s,1H),8.01(dd,J＝7.8,1.2Hz,1H),7.63(t,J＝8.0Hz,1H),7.42-7.38(m,2H),7.26-7.23(m,4H),5.34(s,2H),3.40-3.20(m,4H),2.35-2.29(m,6H),0.97(t,J＝7.1Hz,3H)。MS:m/z393.2[M+H] +。
Embodiment 8
1-(3-(4-benzoyl piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
White solid. 1H?NMR(DMSO-d 6):11.71(s,1H),7.97(d,J＝8.1Hz,1H),7.60-7.56(m,1H),7.45-7.18(m,11H),5.34(s,2H),3.40-3.20(m,8H)。MS:m/z469.3[M+H] +。
Embodiment 9
1-(3-(4-(4-fluorobenzoyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
White solid. 1H?NMR(DMSO-d 6):11.71(s,1H),7.99(d,J＝7.8Hz,1H),7.60-7.19(m,11H),5.34(s,2H),3.60-3.20(m,8H)。MS:m/z487.3[M+H] +。
Embodiment 10
1-(3-(4-(4-chlorobenzoyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
White solid. 1H?NMR(DMSO-d 6):11.73(s,1H),7.98-7.97(m,1H),7.63-7.57(m,1H),7.48-7.19(m,11H),5.33(s,2H),3.75-3.15(m,8H)。MS:m/z503.2，505.2[M+H] +。
Embodiment 11
1-(3-(4-(4-Bromophenacyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
White solid. 1H?NMR(DMSO-d 6):11.74(s,1H),8.02-7.95(m,2H),7.68-7.59(m,2H),7.40-7.15(m,8H),5.35(s,2H),3.40-3.20(m,8H)。MS:m/z547.2[M+H] +。
Embodiment 12
1-(3-(4-(4-methoxybenzoyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
White solid. 1H?NMR(DMSO-d 6):11.73(s,1H),7.99(d,J＝7.2Hz,1H),7.70-7.50(m,1H),7.40-7.29(m,6H),7.21-7.18(m,2H),6.99-6.96(m,2H),5.33(s,2H),3.77(s,3H),3.56-3.15(m,8H)。MS:m/z499.3[M+H] +。
Embodiment 13
1-(3-(4-(tetrahydrochysene-2H-pyrans-4-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
White solid. 1H?NMR(DMSO-d 6):11.74(s,1H),8.02(d,J＝7.5Hz,1H),7.65(t,J＝7.8Hz,1H),7.45-7.38(m,2H),7.32-7.23(m，4H),5.36(s,2H),3.86-3.82(m,2H),3.75-3.10(m,10H),2.90-2.80(m,1H),1.64-1.48(m,4H)。MS:m/z477.3[M+H] +。
Embodiment 14
1-(3-(4-(cyclopentylcarbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
White solid. 1H?NMR(DMSO-d 6):11.71(s,1H),8.01(d,J＝6.9Hz,1H),7.70-7.60(m,1H),7.41-7.39(m,2H),7.30-7.21(m,4H),5.34(s,2H),3.70-3.10(m,8H),2.95-2.89(m,1H),1.80-1.40(m,8H)。MS:m/z461.3[M+H] +。
Embodiment 15
1-(3-(4-(cyclopropyl carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
White solid. 1H?NMR(DMSO-d 6):11.71(s,1H),8.01(d,J＝6.6Hz,1H),7.63(t,J＝7.2Hz,1H),7.41-7.21(m,6H),5.34(s,2H),3.80-3.15(m,8H),1.94-1.91(m,1H),0.72-0.69(m,4H)。MS:m/z433.2[M+H] +。
Embodiment 16
1-(3-(4-(ethylsulfonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
White solid. 1H?NMR(DMSO-d 6):11.74(s,1H),8.01(dd,J＝7.8,1.2Hz,1H),7.70-7.55(m,1H),7.45-7.35(m,2H),7.31-7.19(m,4H),5.35(s,2H),3.75-3.11(m,6H),3.10-2.90(m,4H),1.20(t,J＝7.4Hz,3H)。MS:m/z457.2[M+H] +。
Embodiment 17
1-(3-(4-Acetylpiperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
White solid. 1H?NMR(DMSO-d 6):11.71(s,1H),8.01(d,J＝6.6Hz,1H),7.63(t,J＝7.2Hz,1H),7.43-7.37(m,2H),7.30-7.21(m,4H),5.34(s,2H),3.70-3.10(m,8H),1.93(s,3H)。MS:m/z407.2[M+H] +。
Embodiment 18
1-(3-(4-Phenylpiperidine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
White solid. 1H?NMR(DMSO-d 6):11.75(s,1H),7.99(dd,J＝7.8,1.2Hz,1H),7.61(t,J＝7.2Hz,1H),7.41-7.17(m,11H),5.37(s,2H),3.55-3.42(m,2H),3.06-2.99(m,1H),2.78-2.71(m,2H),1.97-1.51(m,4H)。MS:m/z407.2[M+H] +。
Embodiment 19
1-(3-(4-phenylpiperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
White solid. 1H?NMR(DMSO-d 6):11.75(s,1H),8.03(d,J＝6.6Hz,1H),7.67(t,J＝7.2Hz,1H),7.46-7.39(m,2H),7.34-7.21(m,6H),6.93-6.91(m,2H),6.81(t,J＝7.2Hz,1H),5.37(s,2H),3.85-2.85(m,8H)。MS:m/z441.3[M+H] +。
Embodiment 20
1-(3-(4-(pyrazine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
White solid. 1H?NMR(DMSO-d 6):11.75(s,1H),8.31(s,1H),8.11(s,1H),8.02(d,J＝7.8Hz,1H),7.87(d,J＝2.7Hz,1H),7.67(t,J＝7.2Hz,1H),7.44-7.24(m,6H),5.37(s,2H),3.80-3.25(m,8H)。MS:m/z443.3[M+H] +。
Embodiment 21
1-(the fluoro-3-methoxycarbonyl benzyl of 4-) quinazoline-2,4 (1H, 3H)-diketone
Synthetic method is similar to embodiment 1, and starting raw material is quinazoline-2,4 (1H, 3H)-diketone and 5-(brooethyl)-2-fluorophenyl carbamate.White solid. 1H?NMR(DMSO-d 6):11.75(s,1H),8.00(d,J＝7.8Hz,1H),7.84(d,J＝6.9Hz,1H),7.67-7.55(m,2H),7.32-7.21(m,3H),5.32(s,2H),3.81(s,3H)。MS:m/z329.1[M+H] +。
Embodiment 22
1-(the fluoro-3-carboxybenzyl of 4-) quinazoline-2,4 (1H, 3H)-diketone
Synthetic method is similar to embodiment 2, and starting raw material is 1-(the fluoro-3-methoxycarbonyl benzyl of 4-) quinazoline-2,4 (1H, 3H)-diketone.White solid. 1H?NMR(DMSO-d 6):13.23(brs,1H),11.75(s,1H),8.00(d,J＝7.5Hz,1H),7.80(dd,J＝6.9,2.1Hz,1H),7.67-7.54(m,2H),7.30-7.21(m,3H),5.31(s,2H)。MS:m/z315.3[M+H] +。
The synthetic method that following compound application class is similar to described embodiment 3 obtains, and starting raw material is 1-(4-fluoro-3-carboxybenzyl) quinazoline-2,4 (1H, 3H)-diketone and corresponding substituted-piperazinyl.
Embodiment 23
1-(the fluoro-3-of 4-(4-(cyclopentylcarbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
White solid. 1H?NMR(DMSO-d 6):11.73(s,1H),8.00(d,J＝6.9Hz,1H),7.64(t,J＝7.8Hz,1H),7.43-7.21(m,5H),5.30(s,2H),3.56-2.97(m,8H),2.89-2.84(m,1H),1.80-1.40(m,8H)。MS:m/z479.3[M+H] +。
Embodiment 24
1-(the fluoro-3-of 4-(4-(pyridine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
White solid. 1H?NMR(DMSO-d 6):11.74(s,1H),8.12(d,J＝3.3Hz,1H),8.02(d,J＝6.6Hz,1H),7.67(t,J＝8.4Hz,1H),7.58-7.53(m,1H),7.47-7.39(m,2H),7.32-7.24(m,3H),6.82(d,J＝8.4Hz,1H),6.67(t,J＝6.9Hz,1H),5.32(s,2H),3.75-3.67(m,2H),3.61-3.53(m,2H),3.42-3.37(m.2H),3.28-3.20(m,2H)。MS:m/z460.3[M+H] +。
Embodiment 25
1-(the fluoro-3-of 4-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.72(s,1H),8.37(d,J＝4.8Hz,2H),8.00(d,J＝7.8Hz,1H),7.65(t,J＝6.8Hz,1H),7.48-7.38(m,2H),7.30-7.22(m,3H),6.66(t,J＝4.8Hz,1H),5.31(s,2H),3.70-3.10(m,8H)。MS:m/z461.3[M+H] +。
Following compou nd synthesis method is similar to embodiment 3, and starting raw material is 1-(3-carboxybenzyl) quinazoline-2,4 (1H, 3H)-diketone and corresponding substituted-piperazinyl or piperidines.
Embodiment 26
1-(3-(4-(cyclohexyl-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.75(s,1H),8.02(d,J＝7.8Hz,1H),7.64(t,J＝7.2Hz,1H),7.50-7.45(m,2H),7.35-7.20(m,4H),5.35(s,2H),3.50-3.10(m,9H),1.80-1.25(m,10H)。MS:m/z475.3[M+H] +。
Embodiment 27
1-(3-(4-(benzo [d] isothiazole-3-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.75(s,1H),8.08-8.06(m,2H),8.01(d,J＝7.8Hz,1H),7.87(s,1H),7.67-7.54(m,2H),7.48-7.30(m,5H),7.27-7.20(m,2H),5.37(s,2H),3.80-3.31(m,8H)。MS:m/z498.3[M+H] +。
Embodiment 28
1-(3-(4-(piperidin-1-yl) piperidines-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.76(s,1H),8.03(d,J＝7.2Hz,1H),7.65(t,J＝7.8Hz,1H),7.42-7.21(m,6H),5.41-5.32(m,2H),3.10-2.60(m,9H),1.90-1.30(m,10H)。MS:m/z447.3[M+H] +。
Embodiment 29
1-(3-(4-(pyridin-4-yl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.72(s,1H),8.19(d,J＝6.6Hz,2H),8.02(d,J＝6.3Hz,1H),7.68-7.63(m,1H),7.46-7.39(m,2H),7.34-7.23(m,4H),6.89(d,J＝6.6Hz,2H),5.35(s,2H),3.84-3.31(m,8H)。MS:m/z442.3[M+H] +。
Embodiment 30
1-(3-(4-(cyclobutyl carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.72(s,1H),8.03(d,J＝6.4Hz,1H),7.66(t,J＝7.8Hz,1H),7.46-7.39(m,2H),7.32-7.23(m,4H),5.36(s,2H),3.52-3.31(m,9H),2.19-1.75(m,6H)。MS:m/z447.3[M+H] +。
Embodiment 31
1-(3-(4-(6-fluorobenzene is [d] isoxzzole-3-base also) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.72(s,1H),8.06(dd,J＝8.7,6.4Hz,1H),7.95(dd,J＝7.8,1.5Hz,1H),7.70(dd,J＝9.3,2.1Hz,1H),7.64-7.59(m,1H),7.46-7.14(m,7H),5.36(s,2H),3.45-3.28(m,5H),2.10-2.04(m,1H),1.99-1.94(m,3H)。MS:m/z499.3[M+H] +。
Embodiment 32
1-(3-(4-(thiophene-2-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.70(s,1H),8.00(dd,J＝8.1,1.2Hz,1H),7.76(d,J＝5.1Hz,1H),7.64-7.59(m,1H),7.44-7.11(m,8H),5.34(s,2H),3.81-3.40(m,8H)。MS:m/z475.2[M+H] +。
Embodiment 33
1-(3-(4-(furans-2-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.72(s,1H),8.02(d,J＝6.9Hz,1H),7.86(s,1H),7.65(t,J＝7.5Hz,1H),7.50-7.15(m,6H),7.00(d,J＝3.3Hz,1H),6.70-6.60(m,1H),5.37(s,2H),3.85-3.20(m,8H)。MS:m/z459.2[M+H] +。
Embodiment 34
1-(3-(4-(furans-3-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.71(s,1H),8.15-7.90(m,2H),7.73(s,1H),7.62(t,J＝7.5Hz,1H),7.50-7.10(m,6H),6.64(s,1H),5.34(s,2H),3.80-3.10(m,8H)。MS:m/z459.3[M+H] +。
Embodiment 35
1-(3-(4-(thiophene-3-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.70(s,1H),7.99(d,J＝7.5Hz,1H),7.77(s,1H),7.63-7.58(m,2H),7.41-7.39(m,2H),7.30-7.28(m,2H),7.22-7.17(m,3H),5.34(s,2H),3.81-3.40(m,8H)。MS:m/z475.3[M+H] +。
Embodiment 36
1-(3-(4-(pyridine-3-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.72(s,1H),8.67(dd,J＝4.8,1.5Hz,1H),8.61(s,1H),8.01(d,J＝7.2Hz,1H),7.82(d,J＝6.8Hz,1H),7.52-7.20(m,8H),5.36(s,2H),3.52-3.31(m,8H)。MS:m/z470.3[M+H] +。
Embodiment 37
1-(3-(4-(pyridine-2-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.78(s,1H),8.68(d,J＝4.2Hz,1H),8.20-7.95(m,2H),7.68-7.27(m,9H),5.43(s,2H),3.90-3.50(m,8H)。MS:m/z470.3[M+H] +。
Embodiment 38
1-(3-(4-(pyridine-4-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.62(s,1H),8.58(d,J＝4.2Hz,2H),7.91-7.89(m,1H),7.57-7.44(m,1H),7.29-7.10(m,8H),5.25(s,2H),3.80-2.75(m,8H)。MS:m/z470.3[M+H] +。
Embodiment 39
1-(3-(4-Phenoxypiperidines-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.67(s,1H),7.95(d,J＝8.1Hz,1H),7.57(t,J＝7.8Hz,1H),7.38-7.30(m,2H),7.27-7.14(m,6H),6.92-6.85(m,3H),5.30(s,2H),4.58-4.52(m,1H),3.90-3.10(m,4H),1.95-1.35(m,4H)。MS:m/z456.3[M+H] +。
Following compou nd synthesis method is similar to embodiment 3, and starting raw material is 1-(4-fluoro-3-carboxybenzyl) quinazoline-2,4 (1H, 3H)-diketone and corresponding substituted-piperazinyl.
Embodiment 40
1-(the fluoro-3-of 4-(4-(cyclopropyl carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.72(s,1H),8.01(d,J＝6.6Hz,1H),7.65(t,J＝7.8Hz,1H),7.39-7.22(m,5H),5.31(s,2H),3.52-3.31(m,8H),2.01-1.86(m,1H),0.73-0.70(m,4H)。MS:m/z451.3[M+H] +。
Embodiment 41
1-(the fluoro-3-of 4-(4-(cyclohexyl-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.71(s,1H),8.00(dd,J＝7.8,1.2Hz,1H),7.64(t,J＝7.4Hz,1H),7.43-7.21(m,5H),5.30(s,2H),3.58-3.10(m,9H),1.68-1.00(m,10H)。MS:m/z493.3[M+H] +。
Embodiment 42
1-(the fluoro-3-of 4-(4-(pyrazine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.71(s,1H),8.29(s,1H),8.08(s,1H),8.00(d,J＝7.8Hz,1H),7.86(d,J＝2.1Hz,1H),7.65(t,J＝7.5Hz,1H),7.46-7.36(m,2H),7.30-7.22(m,3H),5.31(s,2H),3.81-3.40(m,8H)。MS:m/z461.3[M+H] +。
Embodiment 43
1-(the fluoro-3-of 4-(4-(benzo [d] isothiazole-3-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.72(s,1H),8.08-8.05(m,2H),8.00(dd,J＝7.8,1.2Hz,1H),7.64(t,J＝7.2Hz,1H),7.56(t,J＝7.7Hz,1H),7.46-7.41(m,3H),7.31-7.19(m,3H),5.31(s,2H),3.87-3.81(m,2H),3.49-3.31(m,6H)。MS:m/z516.2[M+H] +。
Embodiment 44
1-(the fluoro-3-of 4-(4-(cyclobutyl carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.69(s,1H),8.00(d,J＝7.8Hz,1H),7.64(t,J＝8.0Hz,1H),7.44-7.41(m,1H),7.35(d,J＝5.7Hz,1H),7.28-7.21(m,3H),5.30(s,2H),3.70-3.00(m,9H),2.25-1.60(m,6H)。MS:m/z465.3[M+H] +。
Embodiment 45
1-(the fluoro-3-of 4-(4-benzoyl piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.68(s,1H),7.99(d,J＝7.8Hz,1H),7.70-7.10(m,11H),5.30(s,2H),3.80-3.10(m,8H)。MS:m/z487.3[M+H] +。
Embodiment 46
1-(the fluoro-3-of 4-(4-(thiophene-2-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.67(s,1H),8.00(d,J＝7.5Hz,1H),7.75(d,J＝5.1Hz,1H),7.62(t,J＝7.7Hz,1H),7.50-7.15(m,6H),7.12(t,J＝4.4Hz,1H),5.30(s,2H),3.80-3.10(m,8H)。MS:m/z493.2[M+H] +。
Embodiment 47
1-(the fluoro-3-of 4-(4-(furans-2-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.69(s,1H),8.00(d,J＝6.6Hz,1H),7.83(s,1H),7.64(t,J＝7.1Hz,1H),7.50-7.35(m,2H),7.30-7.15(m,3H),6.99(d,J＝3.3Hz,1H),6.70-6.55(m,1H),5.31(s,2H),3.85-3.10(m,8H)。MS:m/z477.3[M+H] +。
Following compou nd synthesis method is similar to embodiment 3, starting raw material is 1-(the chloro-3-carboxybenzyl of 6-) quinazoline-2,4 (1H, (synthetic method is similar to embodiment 1 and 2 to 3H)-diketone, starting raw material is quinazoline-2,4 (1H, 3H)-diketone and 3-(brooethyl)-4-fluorophenyl carbamate) and corresponding substituted-piperazinyl.
Embodiment 48
1-(the fluoro-3-of 6-(4-(cyclopentylcarbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.75(s,1H),8.03(dd,J＝7.8,1.2Hz,1H),7.66(t,J＝7.8Hz,1H),7.38-7.35(m,2H),7.26(t,J＝7.7Hz,1H),7.20-7.15(m,2H),5.35(s,2H),3.38-3.15(m,9H),1.70-1.55(m,8H)。MS:m/z479.3[M+H] +。
Embodiment 49
1-(the fluoro-3-of 6-(4-(cyclohexyl-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.75(s,1H),8.04(d,J＝7.8Hz,1H),7.67(d,J＝7.4Hz,1H),7.50-7.10(m,5H),5.37(s,2H),3.70-2.90(m,9H),1.80-1.00(m,10H)。MS:m/z493.3[M+H] +。
Embodiment 50
1-(the fluoro-3-of 6-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.71(s,1H),8.35(d,J＝4.5Hz,2H),8.01(d,J＝7.6Hz,1H),7.67(t,J＝8.4Hz,1H),7.40-7.17(m,5H),6.64(t,J＝4.8Hz,1H),5.35(s,2H),3.81-3.14(m,8H)。MS:m/z461.2[M+H] +。
Embodiment 51
1-(the fluoro-3-of 6-(4-(pyridine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.72(s,1H),8.12(d,J＝3.3Hz,1H),8.03(d,J＝6.6Hz,1H),7.70(t,J＝8.0Hz,1H),7.56(t,J＝8.0Hz,1H),7.42-7.18(m,5H),6.76(d,J＝8.4Hz,1H),6.67(dd,J＝6.9,5.1Hz,1H),5.38(s,2H),3.70-3.00(m,8H)。MS:m/z460.3[M+H] +。
Embodiment 52
1-(the fluoro-3-of 6-(4-(thiophene-2-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.71(s,1H),8.01(d,J＝8.1Hz,1H),7.76(d,J＝4.8Hz,1H),7.62(t,J＝7.8Hz,1H),7.43-7.32(m,3H),7.22-7.12(m,4H),5.35(s,2H),3.80-2.90(m,8H)。MS:m/z493.2[M+H] +。
Embodiment 53
1-(the fluoro-3-of 6-(4-(cyclobutyl carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.71(s,1H),8.02(d,J＝7.8Hz,1H),7.65(t,J＝8.0Hz,1H),7.36-7.13(m,5H),5.34(s,2H),3.60-2.80(m,9H),2.20-1.70(m,6H)。MS:m/z465.3[M+H] +。
Embodiment 54
1-(the fluoro-3-of 6-(4-(furans-2-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.71(s,1H),8.01(d,J＝6.6Hz,1H),7.84(s,1H),7.64(t,J＝7.5Hz,1H),7.43-7.32(m,2H),7.25-7.16(m,3H),6.96(d,J＝3.0Hz,1H),7.63-6.62(m,1H),5.35(s,2H),3.80-2.90(m,8H)。MS:m/z477.3[M+H] +。
Following compou nd synthesis method is similar to embodiment 3, starting raw material is 1-(the chloro-3-carboxybenzyl of 6-) quinazoline-2,4 (1H, (synthetic method is similar to embodiment 1 and 2 to 3H)-diketone, starting raw material is quinazoline-2,4 (1H, 3H)-diketone and 3-(brooethyl)-4-chloro benzoic ether) and corresponding substituted-piperazinyl.
Embodiment 55
1-(the chloro-3-of 6-(4-(cyclopentylcarbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.75(s,1H),8.05(d,J＝7.8Hz,1H),7.69-7.64(m,2H),7.37(d,J＝8.1Hz,1H),7.28(t,J＝7.3Hz,1H),7.08-7.02(m,2H),5.33(s,2H),3.70-2.80(m,9H),1.80-1.55(m,8H)。MS:m/z495.3[M+H] +。
Embodiment 56
1-(the chloro-3-of 6-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.71(s,1H),8.36(d,J＝4.8Hz,2H),8.03(d,J＝6.6Hz,1H),7.69-7.64(m,2H),7.38(d,J＝6.9Hz,1H),7.28(t,J＝7.5Hz,1H),7.09-7.04(m,2H),6.65(t,J＝4.8Hz,1H),5.33(s,2H),3.80-3.00(m,8H)。MS:m/z477.2[M+H] +。
Embodiment 57
1-(the chloro-3-of 6-(4-(cyclohexyl-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.71(s,1H),8.02(d,J＝7.5Hz,1H),7.75-7.55(m,2H),7.34(d,J＝8.1Hz,1H),7.25(t,J＝7.5Hz,1H),7.10-6.90(m,2H),5.30(s,2H),3.60-2.80(m,9H),1.80-1.00(m,10H)。MS:m/z509.3[M+H] +。
Embodiment 58
1-(the chloro-3-of 6-(4-(pyridine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.73(s,1H),8.11(d,J＝3.6Hz,1H),8.03(d,J＝7.8Hz,1H),7.80-7.60(m,2H),7.55(t,J＝6.9Hz,1H),7.39(d,J＝6.6Hz,1H),7.30(t,J＝7.5Hz,1H),7.15-7.00(m,2H),6.72(d,J＝8.4Hz,1H),6.66(dd,J＝6.8,5.0Hz,1H),5.34(s,2H),3.70-3.00(m,8H)。MS:m/z476.2[M+H] +。
Following compou nd synthesis method is similar to embodiment 3, starting raw material is 1-(the chloro-3-carboxybenzyl of 2-) quinazoline-2,4 (1H, (synthetic method is similar to embodiment 1 and 2 to 3H)-diketone, starting raw material is quinazoline-2,4 (1H, 3H)-diketone and 3-(brooethyl)-2-chloro benzoic ether) and corresponding substituted-piperazinyl.
Embodiment 59
1-(the chloro-3-of 2-(4-(cyclopentylcarbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.78(s,1H),8.07(d,J＝7.8Hz,1H),7.67(t,J＝7.5Hz,1H),7.45-7.20(m,3H),7.15-6.95(m,2H),5.50-5.15(m,2H),3.80-3.10(m,8H),3.04-2.94(m,1H),1.90-1.35(m,8H)。MS:m/z495.3[M+H] +。
Embodiment 60
1-(the chloro-3-of 2-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.88(s,1H),8.49(d,J＝4.8Hz,2H),8.16(d,J＝7.8Hz,1H),7.77(t,J＝7.8Hz,1H),7.50-7.30(m,3H),7.25-7.05(m,2H),6.78(t,J＝7.7Hz,1H),5.60-5.30(m,2H),4.10-3.70(m,8H)。MS:m/z477.2[M+H] +。
Following compou nd synthesis method is similar to embodiment 3, starting raw material is 1-(the fluoro-3-carboxybenzyl of 2-) quinazoline-2,4 (1H, (synthetic method is similar to embodiment 1 and 2 to 3H)-diketone, starting raw material is quinazoline-2,4 (1H, 3H)-diketone and 3-(brooethyl)-2-fluorophenyl carbamate) and corresponding substituted-piperazinyl.
Embodiment 61
1-(the fluoro-3-of 2-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.71(s,1H),8.37(d,J＝4.8Hz,2H),8.03(d,J＝6.6Hz,1H),7.66(t,J＝7.1Hz,1H),7.45-7.05(m,5H),6.66(t,J＝4.7Hz,1H),5.35(s,2H),3.90-3.60(m,8H)。MS:m/z461.3[M+H] +。
Embodiment 62
1-(the fluoro-3-of 2-(4-(cyclopentylcarbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.74(s,1H),8.03(d,J＝7.5Hz,1H),7.66(t,J＝7.7Hz,1H),7.40-7.10(m,5H),5.34(s,2H),3.80-3.20(m,8H),3.10-2.80(m,1H),1.90-1.40(m,8H)。MS:m/z479.3[M+H] +。
Following compou nd synthesis method is similar to embodiment 3, starting raw material is 1-(the fluoro-3-carboxybenzyl of 5-) quinazoline-2,4 (1H, (synthetic method is similar to embodiment 1 and 2 to 3H)-diketone, starting raw material is quinazoline-2,4 (1H, 3H)-diketone and 3-(brooethyl)-5-fluorophenyl carbamate) and corresponding substituted-piperazinyl.
Embodiment 63
1-(the fluoro-3-of 5-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.68(s,1H),8.36(d,J＝4.8Hz,2H),8.00(d,J＝7.8Hz,1H),7.64(t,J＝8.0Hz,1H),7.30-7.15(m,5H),6.64(t,J＝4.8Hz,1H),5.34(s,2H),3.80-3.50(m,8H)。MS:m/z461.3[M+H] +。
Embodiment 64
1-(the fluoro-3-of 5-(4-(cyclopentylcarbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.69(s,1H),8.00(d,J＝9.0Hz,1H),7.64(t,J＝7.1Hz,1H),7.31-7.15(m,5H),5.34(s,2H),3.70-3.10(m,8H),2.94-2.86(m,1H),1.80-1.40(m,8H)。MS:m/z479.3[M+H] +。
Following compou nd synthesis method is similar to embodiment 3, starting raw material is 1-(the chloro-3-carboxybenzyl of 4-) quinazoline-2,4 (1H, (synthetic method is similar to embodiment 1 and 2 to 3H)-diketone, starting raw material is quinazoline-2,4 (1H, 3H)-diketone and 5-(brooethyl)-2-chloro benzoic ether) and corresponding substituted-piperazinyl.
Embodiment 65
1-(the chloro-3-of 4-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(CD 3OD):8.38(d,J＝4.6Hz,2H),8.16(d,J＝9.0Hz,1H),7.69(t,J＝8.7Hz,1H),7.54-7.29(m,5H),6.67(t,J＝4.6Hz,1H),5.51-5.39(m,2H),3.98-3.57(m,8H)。MS:m/z477.2[M+H] +。
Embodiment 66
1-(the chloro-3-of 4-(4-(cyclohexyl-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.60(s,1H),7.91(d,J＝7.8Hz,1H),7.53(t,J＝7.5Hz,1H),7.39(d,J＝9.0Hz,1H),7.28-7.26(m,2H),7.16-7.07(m,2H),5.31-5.13(m,2H),3.48-2.90(m,9H),1.59-1.09(m,10H)。MS:m/z509.3[M+H] +。
Following compou nd synthesis method is similar to embodiment 3, starting raw material is 1-((2-carboxyl furans-5-base) methyl) quinazoline-2,4 (1H, (synthetic method is similar to embodiment 1 and 2 to 3H)-diketone, starting raw material is quinazoline-2,4 (1H, 3H)-diketone and 5-(chloromethyl) furans-2-ethyl formate) and corresponding substituted-piperazinyl.
Embodiment 67
1-((2-(4-(cyclopentylcarbonyl) piperazine-1-carbonyl) furans-5-base) methyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.75(s,1H),8.01(d,J＝7.5Hz,1H),7.74(t,J＝7.5Hz,1H),7.57(d,J＝8.1Hz,1H),7.28(t,J＝7.5Hz,1H),6.96(d,J＝3.3Hz,1H),6.59(d,J＝3.3Hz,1H),5.36(s,2H),3.61-3.14(m,9H),1.73-1.54(m,8H)。MS:m/z451.3[M+1] +。
Embodiment 68
1-((2-(4-(benzo [d] isothiazole-3-base) piperazine-1-carbonyl) furans-5-base) methyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.74(s,1H),8.10-8.08(m,2H),8.02(d,J＝7.8Hz,1H),7.76(t,J＝4.5Hz,1H),7.61-7.57(m,2H),7.48(t,J＝7.5Hz,1H),7.30-7.25(m,1H),7.00(d,J＝3.3Hz,1H),6.60(d,J＝3.3Hz,1H),5.39(s,2H),3.85-3.78(m,4H),3.49-3.40(m,4H)。MS:m/z488.2[M+1] +。
Following compou nd synthesis method is similar to embodiment 3, starting raw material is 1-((2-carboxyl pyridine-6-base) methyl) quinazoline-2,4 (1H, (synthetic method is similar to embodiment 1 and 2 to 3H)-diketone, starting raw material is quinazoline-2,4 (1H, 3H)-diketone and 6-(brooethyl) pyridine-2-methyl-formiate) and corresponding substituted-piperazinyl.
Embodiment 69
1-((2-(4-(cyclopentylcarbonyl) piperazine-1-carbonyl) pyridine-6-base) methyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(CD 3OD):8.16(d,J＝6.3Hz,1H),7.98-7.96(m,1H),7.64-7.59(m,3H),7.32-7.26(m,2H),5.57(s,2H),3.70-3.58(m,4H),3.31-2.92(m,5H),1.84-1.70(m,8H)。MS:m/z462.3[M+H] +。
Embodiment 70
1-((2-(4-(pyridine-2-base) piperazine-1-carbonyl) pyridine-6-base) methyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(CD 3OD):8.15-8.12(m,2H),7.96(t,J＝7.5Hz,1H),7.67-7.58(m,4H),7.30-7.25(m,2H),6.80-6.71(m,2H),5.57(s,2H),3.81-3.78(m,2H),3.59-3.55(m,2H),3.44-3.41(m,2H),3.23-3.19(m,2H)。MS:m/z443.3[M+H] +。
Embodiment 71
1-((2-(4-(pyrimidine-2-base) piperazine-1-carbonyl) pyridine-6-base) methyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(CD 3OD):8.36(d,J＝4.8Hz,2H),8.14(d,J＝6.9Hz,1H),7.96(t,J＝7.5Hz,1H),7.65-7.58(m，3H),7.31-7.28(m,2H),6.64(t,J＝4.8Hz,1H),5.57(s,2H),3.85-3.82(m,2H),3.78-3.73(m,2H),3.57-3.53(m,2H),3.39-3.35(m,2H)。MS:m/z444.3[M+H] +。
Following compou nd synthesis method is similar to embodiment 3, and starting raw material is 1-(3-carboxybenzyl) quinazoline-2,4 (1H, 3H)-diketone and corresponding substituted-piperazinyl.
Embodiment 72
1-(3-(4-(thiazol-2-yl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.72(s,1H),8.03(d,J＝7.3Hz,1H),7.66(t,J＝7.7Hz,1H),7.46-7.23(m,6H),7.18(d,J＝3.6Hz,1H),6.88(d,J＝3.6Hz,1H),5.37(s,2H),3.80-3.40(m,8H)。MS:m/z448.3[M+H] +。
Embodiment 73
1-(3-(4-(cyclohexyl methyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.75(s,1H),8.02(dd,J＝8.0,1.4Hz,1H),7.67-7.62(m,1H),7.41-7.39(m,2H),7.27-7.23(m,4H),5.35(s,2H),3.54-3.15(m,4H),2.32-2.03(m,6H),1.73-1.44(m,5H),1.23-1.06(m,6H)。MS:m/z461.3[M+1] +。
Embodiment 74
1-(3-(4-(cyclopentyl-methyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.73(s,1H),8.03(d,J＝7.5Hz,1H),7.65(d,J＝7.5Hz,1H),7.42-7.23(m,6H),5.36(s,2H),3.54-2.87(m,6H),2.25-2.20(m,4H),1.80-1.24(m,9H)。MS:m/z447.3[M+1] +。
Embodiment 75
1-(3-(4-(cyclohexylsulfonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.69(s,1H),8.01(dd,J＝8.0,1.4Hz,1H),7.64-7.60(m,1H),7.42-7.38(m,2H),7.29-7.16(m,4H),5.35(s,2H),3.56-3.52(m,2H),3.20-3.05(m,6H),1.96-1.93(m,1H),1.80-1.76(m,2H),1.62-1.58(m,2H),1.27-1.22(m,6H)。MS:m/z511.3[M+1] +。
Embodiment 76
7-fluquinconazole quinoline-2,4 (1H, 3H)-diketone
By 2-amino-4-fluorobenzoic acid (4.0g, 26mmol), isocyanic acid potassium (3.5g, 43mmol) and acetic acid (3.0mL, 45mmol) be suspended in 200mL water, at room temperature stir about 5 hours, adds sodium hydroxide (15g, 375mmol), continue stirring 1 hour, then filter and washing leaching cake, then filter cake is suspended in hot water, by acetic acid adjust ph to 5-6, again filter, filter cake washes with water for several times, obtains pale solid target product (3.0g, 65%) after drying.MS:m/z181.1[M+H] +。
Following compou nd synthesis method is similar to embodiment 3, starting raw material is the fluoro-1-of 7-(3-carboxybenzyl) quinazoline-2,4 (1H, (synthetic method is similar to embodiment 1 and 2 to 3H)-diketone, starting raw material is 7-fluquinconazole quinoline-2,4 (1H, 3H)-diketone and 3-(brooethyl) methyl benzoate) and corresponding substituted-piperazinyl.
Embodiment 77
The fluoro-1-of 7-(3-(4-(cyclopentylcarbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.81(s,1H),8.08(t,J＝7.6Hz,1H),7.44-7.31(m,4H),7.18-7.12(m,2H),5.34(s,2H),3.70-2.80(m,9H),1.80-1.55(m,8H)。MS:m/z479.3[M+H] +。
Embodiment 78
The fluoro-1-of 7-(3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.79(s,1H),8.37(d,J＝4.8Hz,2H),8.05(t,J＝7.6Hz,1H),7.45-7.31(m,4H),7.17-7.07(m,2H),6.65(t,J＝4.8Hz,1H),5.33(s,2H),3.78-3.55(m,8H)。MS:m/z461.3[M+H] +。
Following compou nd synthesis method is similar to embodiment 3, starting raw material is 7-methyl isophthalic acid-(3-carboxybenzyl) quinazoline-2,4 (1H, (synthetic method is similar to embodiment 1 and 2 to 3H)-diketone, starting raw material is 7-methylquinazolin-2,4 (1H, 3H)-diketone and 3-(brooethyl) methyl benzoate) and corresponding substituted-piperazinyl.
Embodiment 79
7-methyl isophthalic acid-(3-(4-(cyclopentylcarbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(CD 3OD):8.04(d,J＝8.1Hz,1H),7.51-7.49(m,2H),7.40-7.38(m,2H),7.15-7.11(m,2H),5.45(s,2H),3.75-3.50(m,8H),3.12-3.09(m,1H),2.39(s,3H),1.88-1.64(m,8H)。MS:m/z475.3[M+H] +。
Embodiment 80
7-methyl isophthalic acid-(3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(CD 3OD):8.38-8.36(m,2H),8.04(d,J＝7.8Hz,1H),7.52-7.50(m,2H),7.42-7.40(m,2H),7.16-7.13(m,2H),6.66(t,J＝4.8Hz,1H),5.46(s,2H),3.92-3.56(m,8H),2.40(s,3H)。MS:m/z457.3[M+H] +。
Following compou nd synthesis method is similar to embodiment 3, starting raw material is 6-methyl isophthalic acid-(3-carboxybenzyl) quinazoline-2,4 (1H, (synthetic method is similar to embodiment 1 and 2 to 3H)-diketone, starting raw material is 6-methylquinazolin-2,4 (1H, 3H)-diketone and 3-(brooethyl) methyl benzoate) and corresponding substituted-piperazinyl.
Embodiment 81
6-methyl isophthalic acid-(3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(CD 3OD):8.34(d,J＝4.8Hz,2H),7.94(s,1H),7.49-7.47(m,3H),7.39-7.34(m,2H),7.18(d,J＝8.4Hz,1H),6.64(t,J＝4.8Hz,1H),5.44(s,2H),3.89-3.39(m,8H),2.39(s,3H)。MS:m/z457.3[M+H] +。
Embodiment 82
6-methyl isophthalic acid-(3-(4-(cyclopentylcarbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(CD 3OD):7.95(s,1H),7.49-7.47(m,3H),7.38-7.35(m,2H),7.18(d,J＝8.7Hz,1H),5.43(s,2H),3.71-3.69(m,4H),3.49-3.47(m,4H),3.09-3.08(m,1H),2.39(s,3H),1.88-1.63(m,8H)。MS:m/z475.3[M+H] +。
Following compou nd synthesis method is similar to embodiment 3, starting raw material is 6-methyl isophthalic acid-(the fluoro-3-carboxybenzyl of 4-) quinazoline-2,4 (1H, (synthetic method is similar to embodiment 1 and 2 to 3H)-diketone, starting raw material is 6-methylquinazolin-2,4 (1H, 3H)-diketone and 5-(brooethyl)-2-fluorophenyl carbamate) and corresponding substituted-piperazinyl.
Embodiment 83
6-methyl isophthalic acid-(the fluoro-3-of 4-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(CD 3OD):8.37(d,J＝4.8Hz,2H),7.96(s,1H),7.54-7.51(m,2H),7.40(dd,J＝6.3,2.1Hz,1H),7.28-7.21(m,2H),6.66(t,J＝4.8Hz,1H),5.41(s,2H),3.93-3.56(m,8H),2.41(s,3H)。MS:m/z475.3[M+H] +。
Embodiment 84
6-methyl isophthalic acid-(the fluoro-3-of 4-(4-(cyclohexyl-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.54(s,1H),7.71(s,1H),7.38-7.24(m,3H),7.16(t,J＝9.0Hz,1H),7.04(d,J＝8.7Hz,1H),5.19(s,2H),3.45-2.99(m,9H),2.22(s,3H),1.59-1.49(m,5H),1.22-1.13(m,5H)。MS:m/z507.3[M+H] +。
Embodiment 85
6-methyl isophthalic acid-(the fluoro-3-of 4-(4-(cyclopentylcarbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.63(s,1H),7.80(s,1H),7.46-7.22(m,4H),7.12(d,J＝8.4Hz,1H),5.27(s,2H),3.55-2.97(m,8H),2.99-2.84(m,1H),2.30(s,3H),1.73-1.49(m,8H)。MS:m/z493.3[M+H] +。
Following compou nd synthesis method is similar to embodiment 3, starting raw material is the bromo-1-of 6-(3-carboxybenzyl) quinazoline-2,4 (1H, (synthetic method is similar to embodiment 1 and 2 to 3H)-diketone, starting raw material is 6-bromine quinazoline-2,4 (1H, 3H)-diketone and 3-(brooethyl) methyl benzoate) and corresponding substituted-piperazinyl.
Embodiment 86
The bromo-1-of 6-(3-(4-(cyclohexyl-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.86(s,1H),8.05(d,J＝2.4Hz,1H),7.79(dd,J＝9.0,2.4Hz,1H),7.40-7.38(m,2H),7.30-7.27(m,2H),7.16(d,J＝9.0Hz,1H),5.32(s,2H),3.80-3.11(m,9H),1.68-1.59(m,5H),1.32-1.19(m,5H)。MS:m/z553.3[M+H] +。
Embodiment 87
The bromo-1-of 6-(3-(4-(cyclopentylcarbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.86(s,1H),8.04(d,J＝2.4Hz,1H),7.78(dd,J＝9.0,2.4Hz,1H),7.41-7.38(m,2H),7.29-7.27(m,2H),7.15(d,J＝8.7Hz,1H),5.32(s,2H),3.57-2.90(m,9H),1.71-1.51(m,8H)。MS:m/z539.2[M+H] +。
Embodiment 88
The bromo-1-of 6-(3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(CD 3OD):8.38(d,J＝4.8Hz,2H),8.25-8.24(m,1H),7.78(dd,J＝8.9,2.3Hz,1H),7.52-7.50(m,2H),7.42-7.41(m,2H),7.25(d,J＝9.3Hz,1H),6.66(t,J＝4.6Hz,1H),5.45(s,2H),3.93-3.40(m,8H)。MS:m/z521.2[M+H] +。
Embodiment 89
6-nitro-quinazoline-2,4 (1H, 3H)-diketone
The mixture of 2-amino-5-nitrobenzoic acid (0.588g, 3.23mmol) and urea (1.164g, 19.38mmol) is heated to 200 DEG C, at this temperature and N 2the lower stirring of protection 1 hour.After equitemperature is fallen, add 4N aqueous sodium hydroxide solution and make pH value of solution=14.Then add AcOH and pH is transferred to 5.0.The mixture obtained is filtered, obtains yellow solid target product (0.49g, 72.8%).MS:m/z208.1[M+1] +。
Following compou nd synthesis method is similar to embodiment 3, starting raw material is 6-nitro-1-(3-carboxybenzyl) quinazoline-2,4 (1H, (synthetic method is similar to embodiment 1 and 2 to 3H)-diketone, starting raw material is 6-nitro-quinazoline-2,4 (1H, 3H)-diketone and 3-(brooethyl) methyl benzoate) and corresponding substituted-piperazinyl.
Embodiment 90
6-nitro-1-(3-(4-(cyclopentylcarbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):12.22(s,1H),8.77(d,J＝2.4Hz,1H),8.51(dd,J＝9.3,2.4Hz,1H),7.52-7.46(m,3H),7.43-7.39(m,2H),5.50(s,2H),3.58-2.96(m,9H),1.68-1.31(m,8H)。MS:m/z506.3[M+H] +。
Embodiment 91
6-nitro-1-(3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):12.10(s,1H),8.66(d,J＝2.7Hz,1H),8.44(d,J＝9.3Hz,1H),8.33(d,J＝4.5Hz,2H),7.45-7.39(m,3H),7.34-7.32(m,2H),6.65(t,J＝4.6Hz,1H),5.42(s,2H),3.77-3.46(m,8H)。MS:m/z488.3[M+H] +。
Embodiment 92
6-nitro-1-(3-(4-(cyclohexyl-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):12.21(s,1H),8.77(d,J＝2.7Hz,1H),8.51(dd,J＝9.2,2.6Hz,1H),7.52-7.50(m,3H),7.44-7.39(m,2H),5.50(s,2H),3.68-3.24(m,9H),1.78-1.68(m,5H),1.45-1.23(m,5H)。MS:m/z520.3[M+H] +。
Following compou nd synthesis method is similar to embodiment 3, starting raw material is 1-(4-carboxybenzyl) quinazoline-2,4 (1H, (synthetic method is similar to embodiment 1 and 2 to 3H)-diketone, starting raw material is quinazoline-2,4 (1H, 3H)-diketone and 4-(brooethyl) methyl benzoate) and corresponding substituted-piperazinyl.
Embodiment 93
1-(4-(4-benzoyl piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(CD 3OD):8.17(d,J＝7.5Hz,1H),7.68-7.63(m,1H),7.53-7.41(m,9H),7.30-7.27(m,2H),5.46(s,2H),3.76-3.40(m,8H)。MS:m/z469.2[M+H] +。
Embodiment 94
1-(4-(4-(pyridine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(CD 3OD):8.15(d,J＝8.1Hz,1H),8.11(d,J＝5.1Hz,1H),7.67-7.59(m,2H),7.49-7.43(m,4H),7.32-7.27(m,2H),6.86(d,J＝8.4Hz,1H),6.72(t,J＝6.0Hz,1H),5.46(s,2H),3.85-3.42(m,8H)。MS:m/z442.2[M+H] +。
Embodiment 95
1-(4-(4-(4-methoxybenzoyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(CD 3OD):8.15(d,J＝7.5Hz,1H),7.64(t,J＝7.5Hz,1H),7.43-7.41(m,6H),7.31-7.26(m,2H),7.02-6.99(m,2H),5.45(s,2H),3.84(s,3H),3.80-3.40(m,8H)。MS:m/z499.2[M+H] +。
Embodiment 96
1-(4-(4-(4-fluorobenzoyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(CD 3OD):8.15(d,J＝6.9Hz,1H),7.66-7.61(m,1H),7.59-7.44(m,6H),7.28-7.21(m,4H),5.45(s,2H),3.65-3.40(m,8H)。MS:m/z487.2[M+H] +。
Embodiment 97
1-(4-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(CD 3OD):8.35(d,J＝4.8Hz,2H),8.16(dd,J＝8.0,1.1Hz,1H),7.65(t,J＝6.9Hz,1H),7.49-7.41(m,4H),7.32-7.28(m,2H),6.64(t,J＝4.8Hz,1H),5.46(s,2H),3.80-3.40(m,8H)。MS:m/z443.3[M+H] +。
Embodiment 98
1-(4-(4-(4-Bromophenacyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(CD 3OD):8.16(d,J＝7.8Hz,1H),7.88-7.63(m,3H),7.49-7.39(m,6H),7.32-7.27(m,2H),5.45(s,2H),3.90-3.42(m,8H)。MS:547.2[M+H] +。
Embodiment 99
1-(4-(4-(cyclopentylcarbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(CD 3OD):8.15(dd,J＝8.1,1.5Hz,1H),7.64(t,J＝8.0Hz,1H),7.49-7.42(m,4H),7.31-7.26(m,2H),5.45(s,2H),3.83-3.39(m,8H),3.09-3.00(m,1H),2.02-1.51(m,8H)。MS:461.3[M+H] +。
Following compou nd synthesis method is similar to embodiment 3, starting raw material is the chloro-1-of 5-(3-carboxybenzyl) quinazoline-2,4 (1H, (synthetic method is similar to embodiment 1 and 2 to 3H)-diketone, starting raw material is 5-chloro-quinazoline-2,4 (1H, 3H)-diketone and 3-(brooethyl) methyl benzoate) and corresponding substituted-piperazinyl.
Embodiment 100
The chloro-1-of 5-(3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(CD 3OD):8.38(d,J＝4.8Hz,2H),7.60-7.50(m,3H),7.45-7.39(m,2H),7.35-7.20(m,2H),7.26(d,J＝8.4Hz,1H),6.66(t,J＝4.7Hz,1H),5.48(s,2H),4.00-3.40(m,8H)。MS:m/z477.2[M+H] +。
Embodiment 101
The chloro-1-of 5-(3-(4-(cyclopentylcarbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(CD 3OD):7.60-7.49(m,3H),7.40-7.35(m,2H),7.31(d,J＝9.0Hz,1H),7.23(d,J＝9.0Hz,1H),5.46(s,2H),3.85-2.90(m,9H),2.00-1.55(m,8H)。MS:m/z495.3[M+H] +。
Embodiment 102
The chloro-1-of 5-(3-(4-(cyclohexyl-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.68(s,1H),7.53(t,J＝8.3Hz,1H),7.45-7.39(m,2H),7.30-7.20(m,3H),7.15(d,J＝8.7Hz,1H),5.34(s,2H),3.70-3.00(m,9H),1.80-1.00(m,10H)。MS:m/z509.3[M+H] +。
Following compou nd synthesis method is similar to embodiment 3, starting raw material is the chloro-1-of 5-(the fluoro-3-carboxybenzyl of 4-) quinazoline-2,4 (1H, (synthetic method is similar to embodiment 1 and 2 to 3H)-diketone, starting raw material is 5-chloro-quinazoline-2,4 (1H, 3H)-diketone and 5-(brooethyl)-2-fluorophenyl carbamate) and corresponding substituted-piperazinyl.
Embodiment 103
The chloro-1-of 5-(the fluoro-3-of 4-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.69(s,1H),8.39(d,J＝4.5Hz,2H),7.50(t,J＝7.8Hz,1H),7.47-7.39(m,2H),7.32-7.25(m,2H),7.20(d,J＝9.0Hz,1H),6.67(t,J＝4.5Hz,1H),5.32(s,2H),3.81-3.33(m,8H)。MS:m/z495.2[M+H] +。
Embodiment 104
The chloro-1-of 5-(the fluoro-3-of 4-(4-(cyclopentylcarbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.69(s,1H),7.58(t,J＝7.8Hz,1H),7.47-7.42(m,1H),7.38(d,J＝6.0Hz,1H),7.31-7.25(m,2H),7.18-7.14(m,1H),5.31(s,2H),3.70-3.00(m,9H),1.85-1.40(m,8H)。MS:m/z513.3[M+H] +。
Embodiment 105
The chloro-1-of 5-(the fluoro-3-of 4-(4-(cyclohexyl-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.67(s,1H),7.53(t,J＝8.3Hz,1H),7.45-7.41(m,1H),7.35(dd,J＝6.2,2.0Hz,1H),7.31-7.20(m,2H),7.15(s,1H),5.29(s,2H),3.70-3.00(m,9H),1.80-1.00(m,10H)。MS:m/z527.3[M+H] +。
Embodiment 106
The chloro-1-of 5-(the fluoro-3-of 4-(4-(pyridine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.66(s,1H),8.11(d,J＝1.8Hz,1H),7.57-7.52(m,2H),7.45-7.37(m,2H),7.31-7.20(m,2H),7.17(d,J＝8.7Hz,1H),6.81(d,J＝8.7Hz,1H),6.56(t,J＝6.0Hz,1H),5.30(s,2H),3.80-3.10(m,8H)。MS:m/z494.2[M+H] +。
Embodiment 107
The chloro-1-of 5-(the fluoro-3-of 4-(4-(thiophene-2-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.68(s,1H),7.76(dd,J＝5.0,1.1Hz,1H),7.46(t,J＝8.4Hz,1H),7.49-7.36(m,3H),7.30-7.19(m,2H),7.15-7.05(m,2H),5.30(s,2H),3.80-3.15(m,8H)。MS:m/z527.2[M+H] +。
Following compou nd synthesis method is similar to embodiment 3, starting raw material is the chloro-1-of 5-(the fluoro-3-carboxybenzyl of 6-) quinazoline-2,4 (1H, (synthetic method is similar to embodiment 1 and 2 to 3H)-diketone, starting raw material is 5-chloro-quinazoline-2,4 (1H, 3H)-diketone and 3-(brooethyl)-4-fluorophenyl carbamate) and corresponding substituted-piperazinyl.
Embodiment 108
The chloro-1-of 5-(the fluoro-3-of 6-(4-(cyclohexyl-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.70(s,1H),7.55(t,J＝8.7Hz,1H),7.45-7.34(m,2H),7.27(d,J＝7.5Hz,1H),7.17(d,J＝6.9Hz,1H),7.13(d,J＝7.8Hz,1H),5.33(s,2H),3.80-3.00(m,9H),1.80-1.10(m,10H)。MS:m/z527.3[M+H] +。
Embodiment 109
The chloro-1-of 5-(the fluoro-3-of 6-(4-(cyclopentylcarbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.71(s,1H),7.57(t,J＝8.3Hz,1H),7.45-7.25(m,3H),7.20(d,J＝7.5Hz,1H),7.14(d,J＝8.7Hz,1H),5.35(s,2H),3.70-2.80(m,9H),1.85-1.40(m,8H)。MS:m/z513.3[M+H] +。
Embodiment 110
The chloro-1-of 5-(the fluoro-3-of 6-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.68(s,1H),8.35(d,J＝4.5Hz,2H),7.56(t,J＝8.4Hz,1H),7.45-7.27(m,3H),7.22(d,J＝6.6Hz,1H),7.15(d,J＝8.7Hz,1H),6.64(t,J＝4.5Hz,1H),5.34(s,2H),3.80-3.10(m,8H)。MS:m/z495.3[M+H] +。
Following compou nd synthesis method is similar to embodiment 3, starting raw material is the chloro-1-of 6-(3-carboxybenzyl) quinazoline-2,4 (1H, (synthetic method is similar to embodiment 1 and 2 to 3H)-diketone, starting raw material is 6-chloro-quinazoline-2,4 (1H, 3H)-diketone and 3-(brooethyl) methyl benzoate) and corresponding substituted-piperazinyl.
Embodiment 111
The chloro-1-of 6-(3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(CD 3OD):8.37(d,J＝4.8Hz,2H),8.09(d,J＝2.7Hz,1H),7.64(dd,J＝9.2,2.6Hz,1H),7.55-7.45(m,2H),7.45-7.35(m,2H),7.32(d,J＝9.0Hz,1H),6.66(t,J＝4.7Hz,1H),5.45(s,2H),4.00-3.33(m,8H)。MS:m/z477.2[M+H] +。
Embodiment 112
The chloro-1-of 6-(3-(4-(cyclopentylcarbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.87(s,1H),7.94(d,J＝2.7Hz,1H),7.70(dd,J＝9.0,2.7Hz,1H),7.46-7.38(m,2H),7.31-7.23(m,3H),5.35(s,2H),3.70-2.80(m,9H),1.90-1.40(m,8H)。MS:m/z495.2[M+H] +。
Embodiment 113
The chloro-1-of 6-(3-(4-(cyclohexyl-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.88(s,1H),7.94(d,J＝2.4Hz,1H),7.74(dd,J＝9.0,2.4Hz,1H),7.46-7.37(m,2H),7.32-7.23(m,3H),5.35(s,2H),3.80-3.10(m,9H),1.80-1.10(m,10H)。MS:m/z509.3[M+H] +。
Embodiment 114
The chloro-1-of 6-(3-(4-(pyridine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.95(s,1H),8.21-8.20(m,1H),8.02(s,1H),7.82-7.78(m,1H),7.66-7.60(m,1H),7.49-7.42(m,5H),6.89(d,J＝3.0Hz,1H),6.75(t,J＝6.0Hz,1H),5.44(s,2H),3.85-3.29(m,8H)。MS:m/z476.3[M+H] +。
Embodiment 115
The chloro-1-of 6-(3-(4-(thiophene-2-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.87(s,1H),7.92(d,J＝2.7Hz,1H),7.76(d,J＝4.8Hz,1H),7.67(dd,J＝8.9,2.6Hz,1H),7.50-7.35(m,3H),7.32-7.29(m,2H),7.23(d,J＝9.0Hz,1H),7.12(dd,J＝4.8,3.6Hz,1H),5.33(s,2H),3.79-3.45(m,8H)。MS:m/z509.2[M+H] +。
Embodiment 116
The chloro-1-of 6-(3-(4-(cyclobutyl carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.87(s,1H),7.93(d,J＝2.4Hz,1H),7.68(dd,J＝9.0,2.4Hz,1H),7.43-7.35(m,2H),7.31-7.22(m,3H),5.33(s,2H),3.60-3.00(m,9H),2.20-1.60(m,6H)。MS:m/z481.3[M+H] +。
Following compou nd synthesis method is similar to embodiment 3, starting raw material is the chloro-1-of 6-(the fluoro-3-carboxybenzyl of 4-) quinazoline-2,4 (1H, (synthetic method is similar to embodiment 1 and 2 to 3H)-diketone, starting raw material is 6-chloro-quinazoline-2,4 (1H, 3H)-diketone and 5-(brooethyl)-2-fluorophenyl carbamate) and corresponding substituted-piperazinyl.
Embodiment 117
The chloro-1-of 6-(the fluoro-3-of 4-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.84(s,1H),8.37(d,J＝4.8Hz,2H),7.92(s,1H),7.69(dd,J＝8.9,2.6Hz,1H),7.47-7.36(m,2H),7.30-7.24(m,2H),6.65(t,J＝4.8Hz,1H),5.30(s,2H),3.78-3.21(m,8H)。MS:m/z495.2[M+H] +。
Embodiment 118
The chloro-1-of 6-(the fluoro-3-of 4-(4-(cyclopentylcarbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.85(s,1H),7.92(d,J＝2.4Hz,1H),7.68(dd,J＝9.0,2.4Hz,1H),7.44-7.41(m,1H),7.36-7.34(m,1H),7.30-7.15(m,2H),5.29(s,2H),3.70-2.80(m,9H),1.80-1.40(m,8H)。MS:m/z513.3[M+H] +。
Embodiment 119
The chloro-1-of 6-(the fluoro-3-of 4-(4-(cyclohexyl-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.85(s,1H),7.92(d,J＝2.1Hz,1H),7.68(dd,J＝8.7,2.4Hz,1H),7.45-7.39(m,1H),7.35(d,J＝5.4Hz,1H),7.31-7.15(m,2H),5.29(s,2H),3.70-3.00(m,9H),1.80-1.10(m,10H)。MS:m/z527.3[M+H] +。
Embodiment 120
The chloro-1-of 6-(the fluoro-3-of 4-(4-(pyridine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):8.10(d,J＝3.6Hz,1H),7.92(s,1H),7.69(d,J＝9.0Hz,1H),7.54(t,J＝9.0Hz,1H),7.45-7.36(m,2H),7.30-7.23(m,2H),6.81(d,J＝7.8Hz,1H),6.66(t,J＝6.3Hz,1H),5.30(s,2H),3.68-3.21(m,8H)。MS:m/z494.2[M+H] +。
Embodiment 121
The chloro-1-of 6-(the fluoro-3-of 4-(4-(thiophene-2-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.86(s,1H),7.92(d,J＝2.4Hz,1H),7.76(d,J＝4.2Hz,1H),7.68(dd,J＝9.0,2.4Hz,1H),7.46-7.36(m,3H),7.30-7.22(m,2H),7.12(dd,J＝5.0,3.8Hz,1H),5.30(s,2H),3.68-3.21(m,8H)。MS:m/z527.2[M+H] +。
Embodiment 122
The chloro-1-of 6-(the fluoro-3-of 4-(4-(cyclopropyl carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.85(s,1H),7.94(s,1H),7.70(dd,J＝8.4,2.1Hz,1H),7.47-7.23(m,4H),5.31(s,2H),3.59-3.09(m,8H),2.01-1.96(m,1H),0.77-0.69(m,4H)。MS:m/z485.3[M+H] +。
Following compou nd synthesis method is similar to embodiment 3, starting raw material is the chloro-1-of 6-(the fluoro-3-carboxybenzyl of 6-) quinazoline-2,4 (1H, (synthetic method is similar to embodiment 1 and 2 to 3H)-diketone, starting raw material is 6-chloro-quinazoline-2,4 (1H, 3H)-diketone and 3-(brooethyl)-4-fluorophenyl carbamate) and corresponding substituted-piperazinyl.
Embodiment 123
The chloro-1-of 6-(the fluoro-3-of 6-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.88(s,1H),8.36(d,J＝4.5Hz,2H),7.93(d,J＝2.4Hz,1H),7.73(dd,J＝9.0,2.4Hz,1H),7.36-7.20(m,4H),6.65(t,J＝4.8Hz,1H),5.37(s,2H),3.78-3.21(m,8H)。MS:m/z495.2[M+H] +。
Embodiment 124
The chloro-1-of 6-(the fluoro-3-of 6-(4-(cyclopentylcarbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.87(s,1H),7.94(d,J＝2.4Hz,1H),7.71(dd,J＝9.2,2.3Hz,1H),7.42-7.32(m,2H),7.23-7.17(m,2H),5.34(s,2H),3.59-3.09(m,9H),1.71-1.56(m,8H)。MS:m/z513.3[M+H] +。
Embodiment 125
The chloro-1-of 6-(the fluoro-3-of 6-(4-(cyclohexyl-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.87(s,1H),7.93(d,J＝2.4Hz,1H),7.70(dd,J＝8.9,2.6Hz,1H),7.41-7.31(m,2H),7.22-7.16(m,2H),5.33(s,2H),3.54-3.10(m,9H),1.70-1.15(m,10H)。MS:m/z527.3[M+H] +。
Embodiment 126
The chloro-1-of 6-(the fluoro-3-of 6-(4-(thiophene-2-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.86(s,1H),7.93(d,J＝2.4Hz,1H),7.76(d,J＝4.8Hz,1H),7.67(dd,J＝9.0,1.8Hz,1H),7.43-7.32(m,3H),7.22-7.19(m,2H),7.12(t,J＝4.2Hz,1H),5.33(s,2H),3.54-3.19(m,8H)。MS:m/z527.2[M+H] +。
Following compou nd synthesis method is similar to embodiment 3, starting raw material is the fluoro-1-of 5-(3-carboxybenzyl) quinazoline-2,4 (1H, (synthetic method is similar to embodiment 1 and 2 to 3H)-diketone, starting raw material is 5-fluquinconazole quinoline-2,4 (1H, 3H)-diketone and 3-(brooethyl) methyl benzoate) and corresponding substituted-piperazinyl.
Embodiment 127
The fluoro-1-of 5-(3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(CD 3OD):8.35(d,J＝4.8Hz,2H),7.61(td,J＝8.4,5.7Hz,1H),7.50-7.32(m,4H),7.06(d,J＝8.4Hz,1H),6.99(dd,J＝10.8,8.4Hz,1H),6.64(t,J＝4.8Hz,1H),5.48(s,2H),3.89-3.38(m,8H)。MS:m/z461.2[M+H] +。
Embodiment 128
The fluoro-1-of 5-(3-(4-(cyclopentylcarbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.67(s,1H),7.65-7.57(m,1H),7.41-7.39(m,2H),7.31-7.27(m,2H),7.05-6.97(m,2H),5.32(s,2H),3.69-2.90(m,9H),1.81-1.51(m,8H)。MS:m/z479.3[M+H] +。
Embodiment 129
The fluoro-1-of 5-(3-(4-(cyclohexyl-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.69(s,1H),7.62(td,J＝8.4,6.0Hz,1H),7.46-7.41(m,2H),7.32-7.29(m,2H),7.05-6.99(m,2H),5.34(s,2H),3.79-3.11(m,9H),1.71-1.61(m,5H),1.33-1.17(m,5H)。MS:m/z493.3[M+H] +。
Embodiment 130
The fluoro-1-of 5-(3-(4-(pyridine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.67(s,1H),8.10(d,J＝3.6Hz,1H),7.66-7.51(m,2H),7.44-7.29(m,4H),7.04-6.98(m,2H),6.80(d,J＝8.7Hz,1H),6.64(t,J＝6.6Hz,1H),5.33(s,2H),3.79-3.41(m,8H)。MS:m/z460.3[M+H] +。
Embodiment 131
The fluoro-1-of 5-(3-(4-(thiophene-2-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.67(s,1H),7.77(d,J＝5.1Hz,1H),7.59(td,J＝8.4,6.0Hz,1H),7.44-7.29(m,5H),7.14(d,J＝3.9Hz,1H),7.02-6.95(m,2H),5.33(s,2H),3.64-3.41(m,8H)。MS:m/z493.2[M+H] +。
Following compou nd synthesis method is similar to embodiment 3, starting raw material is the fluoro-1-of 5-(the fluoro-3-carboxybenzyl of 4-) quinazoline-2,4 (1H, (synthetic method is similar to embodiment 1 and 2 to 3H)-diketone, starting raw material is 5-fluquinconazole quinoline-2,4 (1H, 3H)-diketone and 5-(brooethyl)-2-fluorophenyl carbamate) and corresponding substituted-piperazinyl.
Embodiment 132
The fluoro-1-of 5-(the fluoro-3-of 4-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.65(s,1H),8.38(d,J＝4.8Hz,2H),7.95-7.66(m,1H),7.47-7.38(m,2H),7.28(t,J＝9.0Hz,1H),7.05-6.99(m,2H),6.66(t,J＝4.8Hz,1H),5.30(s,2H),3.82-3.79(m,2H),3.69-3.61(m,4H),3.23-3.21(m,2H)。MS:m/z479.2[M+H] +。
Embodiment 133
The fluoro-1-of 5-(the fluoro-3-of 4-(4-(cyclopentylcarbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.66(s,1H),7.65-7.58(m,1H),7.47-7.41(m,1H),7.38(d,J＝5.7Hz,1H),7.27(t,J＝9.0Hz,1H),7.05-6.98(m,2H),5.29(s,2H),3.59-2.89(m,9H),1.79-1.45(m,8H)。MS:m/z497.3[M+H] +。
Embodiment 134
The fluoro-1-of 5-(the fluoro-3-of 4-(4-(cyclohexyl-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.67(s,1H),7.66-7.59(m,1H),7.47-7.43(m,1H),7.38(d,J＝6.0Hz,1H),7.28(t,J＝8.9Hz,1H),7.05-6.99(m,2H),5.30(s,2H),3.55-3.12(m,9H),1.62-1.06(m,10H)。MS:m/z511.3[M+H] +。
Embodiment 135
The fluoro-1-of 5-(the fluoro-3-of 4-(4-(pyridine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.65(s,1H),8.11(dd,J＝5.0,1.7Hz,1H),7.70-7.50(m,2H),7.48-7.37(m,2H),7.27(t,J＝9.0Hz,1H),7.04-6.98(m,2H),6.81(d,J＝8.7Hz,1H),6.66(t,J＝5.7Hz,1H),5.29(s,2H),3.70-3.68(m,2H),3.57-3.54(m,2H),3.38-3.34(m,2H),3.24-3.22(m,2H)。MS:m/z478.2[M+H] +。
Embodiment 136
The fluoro-1-of 5-(the fluoro-3-of 4-(4-(thiophene-2-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.64(s,1H),7.77(d,J＝4.8Hz,1H),7.64-7.56(m,1H),7.46-7.37(m,3H),7.27(t,J＝9.0Hz,1H),7.13(t,J＝4.8Hz,1H),7.02-6.97(m,2H),5.30(s,2H),3.70-3.23(m,8H)。MS:m/z511.2[M+H] +。
Embodiment 137
The fluoro-1-of 5-(the fluoro-3-of 4-(4-benzoyl piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.67(s,1H),7.60-7.27(m,9H),7.05-6.95(m,2H),5.30(s,2H),3.66-3.29(m,8H)。MS:m/z505.3[M+H] +。
The compou nd synthesis method of embodiment 138 is similar to embodiment 3, starting raw material is the fluoro-1-of 8-(3-carboxybenzyl) quinazoline-2,4 (1H, (synthetic method is similar to embodiment 1 and 2 to 3H)-diketone, starting raw material is 8-fluquinconazole quinoline-2,4 (1H, 3H)-diketone and 3-(brooethyl) methyl benzoate) and corresponding substituted-piperazinyl.
Embodiment 138
The fluoro-1-of 8-(3-(4-(cyclohexyl-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.90(s,1H),7.91(d,J＝7.2Hz,1H),7.59-7.51(m,1H),7.44-7.33(m,2H),7.29-7.28(m,3H),5.40(s,2H),3.59-3.19(m,9H),1.61-1.24(m,10H).MS:m/z493.3[M+H] +。
Following compou nd synthesis method is similar to embodiment 3, starting raw material is the fluoro-1-of 6-(3-carboxybenzyl) quinazoline-2,4 (1H, (synthetic method is similar to embodiment 1 and 2 to 3H)-diketone, starting raw material is 6-fluquinconazole quinoline-2,4 (1H, 3H)-diketone and 3-(brooethyl) methyl benzoate) and corresponding substituted-piperazinyl.
Embodiment 139
The fluoro-1-of 6-(3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.86(s,1H),8.38(d,J＝4.5Hz,2H),7.73(dd,J＝8.1,3.0Hz,1H),7.57(td,J＝9.0,3.3Hz,1H),7.36-7.27(m,5H),6.67(t,J＝4.7Hz,1H),5.36(s,2H),3.65-3.30(m,8H)。MS:m/z461.2[M+H] +。
Embodiment 140
The fluoro-1-of 6-(3-(4-(pyridine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.85(s,1H),8.13(d,J＝3.3Hz,1H),7.73(dd,J＝8.4,3.0Hz,1H),7.61-7.53(m,2H),7.46-7.38(m,2H),7.35-7.28(m,3H),6.82(d,J＝8.4Hz,1H),6.67(t,J＝4.8Hz,1H),5.36(s,2H),3.76-3.33(m,8H)。MS:m/z460.3[M+H] +。
Embodiment 141
The fluoro-1-of 6-(3-(4-(thiophene-2-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.85(s,1H),7.77-7.76(m,2H),7.73(dd,J＝8.4,3.0Hz,1H),7.54-7.14(m,6H),7.13(t,J＝4.4Hz,1H),5.35(s,2H),3.66-3.30(m,8H)。MS:m/z493.2[M+H] +。
Embodiment 142
The fluoro-1-of 6-(3-(4-(cyclohexyl-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.86(s,1H),7.74(dd,J＝8.1,3.0Hz,1H),7.56(m,1H),7.43-7.41(m,2H),7.32-7.29(m,3H),5.36(s,2H),3.60-3.10(m,9H),1.61-1.29(m,10H)。MS:m/z493.3[M+H] +。
Embodiment 143
The fluoro-1-of 6-(3-(4-(cyclopentylcarbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(CD 3OD):7.84(dd,J＝8.4,3.0Hz,1H),7.52-7.43(m,5H),7.34(dd,J＝9.2,4.1Hz,1H),5.46(s,2H),3.72-3.11(m,9H),1.88-1.66(m,8H)。MS:m/z479.3[M+H] +。
Following compou nd synthesis method is similar to embodiment 3, starting raw material is the fluoro-1-of 6-(the fluoro-3-carboxybenzyl of 4-) quinazoline-2,4 (1H, (synthetic method is similar to embodiment 1 and 2 to 3H)-diketone, starting raw material is 6-fluquinconazole quinoline-2,4 (1H, 3H)-diketone and 5-(brooethyl)-2-fluorophenyl carbamate) and corresponding substituted-piperazinyl.
Embodiment 144
The fluoro-1-of 6-(the fluoro-3-of 4-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.83(s,1H),8.39(d,J＝4.8Hz,2H),7.74(dd,J＝8.4,3.0Hz,1H),7.60-7.54(m,1H),7.41-7.29(m,4H),6.67(t,J＝4.8Hz,1H),5.32(s,2H),3.81-3.23(m,8H)。MS:m/z479.3[M+H] +。
Embodiment 145
The fluoro-1-of 6-(the fluoro-3-of 4-(4-(pyridine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.85(s,1H),8.12(dd,J＝4.8,1.5Hz,1H),7.72(dd,J＝8.3,3.2Hz,1H),7.60-7.53(m,2H),7.47-7.40(m,2H),7.32-7.26(m,2H),6.83(d,J＝8.7Hz,1H),6.68(dd,J＝6.9,5.1Hz,1H),5.33(s,2H),3.72-3.25(m,8H)。MS:m/z478.3[M+H] +。
Embodiment 146
The fluoro-1-of 6-(the fluoro-3-of 4-(4-(thiophene-2-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.83(s,1H),7.77-7.70(m,2H),7.57-7.51(m,1H),7.41-7.37(m,3H),7.31-7.25(m,2H),7.12(t,J＝4.2Hz,1H),5.31(s,2H),3.70-3.16(m,8H)。MS:m/z511.2[M+H] +。
Embodiment 147
The fluoro-1-of 6-(the fluoro-3-of 4-(4-(cyclohexyl-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.83(s,1H),7.72(dd,J＝8.3,3.2Hz,1H),7.57-7.50(m,1H),7.45-7.41(m,1H),7.36(d,J＝6.3Hz,1H),7.29-7.23(m,2H),5.30(s,2H),3.53-3.10(m,9H),1.60-1.21(m,10H)。MS:m/z511.3[M+H] +。
Embodiment 148
The fluoro-1-of 6-(the fluoro-3-of 4-(4-(cyclopentylcarbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.83(s,1H),7.73(dd,J＝8.4,3.0Hz,1H),7.55(t,J＝8.4Hz,1H),7.46-7.42(m,1H),7.36(d,J＝6.0Hz,1H),7.30-7.24(m,2H),5.31(s,2H),3.56-3.12(m,9H),1.60-1.56(m,8H)。MS:m/z479.3[M+H] +。
Following compou nd synthesis method is similar to embodiment 3, starting raw material is the fluoro-1-of 6-(the fluoro-3-carboxybenzyl of 6-) quinazoline-2,4 (1H, (synthetic method is similar to embodiment 1 and 2 to 3H)-diketone, starting raw material is 6-fluquinconazole quinoline-2,4 (1H, 3H)-diketone and 3-(brooethyl)-4-fluorophenyl carbamate) and corresponding substituted-piperazinyl or piperidines.
Embodiment 149
The fluoro-1-of 6-(the fluoro-3-of 6-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.85(s,1H),8.38(d,J＝4.5Hz,2H),7.74(dd,J＝8.3,3.2Hz,1H),7.62-7.55(m,1H),7.39-7.33(m,2H),7.30-7.20(m,2H),6.66(t,J＝4.8Hz,1H),5.37(s,2H),3.65-3.30(m,8H)。MS:m/z479.3[M+H] +。
Embodiment 150
The fluoro-1-of 6-(the fluoro-3-of 6-(4-(pyridine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.85(s,1H),8.12(d,J＝3.3Hz,1H),7.74(d,J＝8.4Hz,1H),7.63-7.52(m,2H),7.40-7.26(m,3H),7.21(d,J＝7.2Hz,1H),6.77(d,J＝8.4Hz,1H),6.66(t,J＝5.9Hz,1H),5.37(s,2H),3.51-3.32(m,8H)。MS:m/z478.3[M+H] +。
Embodiment 151
The fluoro-1-of 6-(the fluoro-3-of 6-(4-(thiophene-2-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.83(s,1H),7.75-7.69(m,2H),7.52-7.49(m,1H),7.39-7.30(m,3H),7.23-7.17(m,2H),7.11(t,J＝4.2Hz,1H),5.33(s,2H),3.70-3.13(m,8H)。MS:m/z511.2[M+H] +。
Embodiment 152
The fluoro-1-of 6-(the fluoro-3-of 6-(4-(cyclohexyl-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.86(s,1H),7.76(dd,J＝8.1,3.0Hz,1H),7.60-7.54(m,1H),7.39-7.35(m,2H),7.24(dd,J＝9.2,4.1Hz,1H),7.18(d,J＝6.9Hz,1H),5.36(s,2H),3.53-3.10(m,9H),1.70-1.25(m,10H)。MS:m/z511.3[M+H] +。
Embodiment 153
The fluoro-1-of 6-(the fluoro-3-of 6-(4-(cyclopentylcarbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):7.72(dd,J＝8.6,3.9Hz,1H),7.58-7.51(m,1H),7.36-7.33(m,2H),7.23(dd,J＝9.5,3.8Hz,1H),7.16(d,J＝7.2Hz,1H),5.33(s,2H),3.31-2.63(m,9H),1.73-1.43(m,8H)。MS:m/z479.3[M+H] +。
Following compou nd synthesis method is similar to embodiment 3, and starting raw material is the fluoro-1-of 5-(6-fluoro-3-carboxybenzyl) quinazoline-2,4 (1H, 3H)-diketone and corresponding substituted-piperazinyl.
Embodiment 154
The fluoro-1-of 5-(the fluoro-3-of 6-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.68(s,1H),8.38(d,J＝4.5Hz,2H),7.67-7.65(m,1H),7.40-7.33(m,2H),7.21(d,J＝7.2Hz,1H),7.08-7.00(m,2H),6.66(t,J＝4.8Hz,1H),5.35(s,2H),3.81-3.23(m,8H)。MS:m/z479.3[M+H] +。
Embodiment 155
The fluoro-1-of 5-(the fluoro-3-of 6-(4-(pyridine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.66(s,1H),8.10(d,J＝3.3Hz,1H),7.69-7.61(m,1H),7.53(t,J＝6.9Hz,1H),7.40-7.31(m,2H),7.21(d,J＝6.6Hz,1H),7.08-6.99(m,2H),6.76(d,J＝8.7Hz,1H),6.65(t,J＝6.9Hz,1H),5.34(s,2H),3.51-3.30(m,8H)。MS:m/z478.3[M+H] +。
Embodiment 156
The fluoro-1-of 5-(the fluoro-3-of 6-(4-(thiophene-2-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.69(s,1H),7.78(d,J＝4.5Hz,1H),7.64-7.60(m,1H),7.38-7.35(m,3H),7.22(d,J＝6.0Hz,1H),7.16-7.13(m,1H),7.00-6.94(m,2H),5.33(s,2H),3.32-3.15(m,8H)。MS:m/z511.2[M+H] +。
Embodiment 157
The fluoro-1-of 5-(the fluoro-3-of 6-(4-(cyclohexyl-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.70(s,1H),7.68-7.61(m,1H),7.39-7.33(m,2H),7.21(d,J＝7.2Hz,1H),7.06-6.97(m,2H),5.34(s,2H),3.53-3.10(m,9H),1.70-1.24(m,10H)。MS:m/z511.3[M+H] +。
Embodiment 158
The fluoro-1-of 5-(the fluoro-3-of 6-(4-(cyclopentylcarbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.68(s,1H),7.67-7.60(m,1H),7.41-7.32(m,2H),7.20(d,J＝7.5Hz,1H),7.06-6.97(m,2H),5.33(s,2H),3.60-3.15(m,9H),1.60-1.55(m,8H)。MS:m/z497.3[M+H] +。
Following compou nd synthesis method is similar to embodiment 3, and starting raw material is 5-methyl isophthalic acid-(3-carboxybenzyl) quinazoline-2,4 (1H, 3H)-diketone and corresponding substituted-piperazinyl.
Embodiment 159
5-methyl isophthalic acid-(3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(CD 3OD):8.37(d,J＝4.8Hz,2H),7.49-7.47(m,3H),7.42-7.36(m,2H),7.14-7.08(m,2H),6.66(t,J＝5.0Hz,1H),5.46(s,2H),3.91-3.62(m,8H),2.79(s,3H)。MS:m/z457.3[M+H] +。
Embodiment 160
5-methyl isophthalic acid-(3-(4-(cyclopentylcarbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(CD 3OD):7.49-7.36(m,5H),7.14-7.08(m,2H),5.46(s,2H),3.82-3.10(m,9H),2.80(s,3H),1.88-1.56(m,8H)。MS:m/z475.3[M+H] +。
Following compou nd synthesis method is similar to embodiment 3, and starting raw material is the chloro-1-of 7-(3-carboxybenzyl) quinazoline-2,4 (1H, 3H)-diketone and corresponding substituted-piperazinyl.
Embodiment 161
The chloro-1-of 7-(3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.81(s,1H),8.37(d,J＝4.8Hz,2H),8.00(d,J＝8.4Hz,1H),7.40-7.27(m,6H),6.65(t,J＝4.7Hz,1H),5.36(s,2H),3.77-3.63(m,8H)。MS:m/z477.2[M+H] +。
Embodiment 162
The chloro-1-of 7-(3-(4-(cyclopentylcarbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.85(s,1H),8.02(d,J＝9.0Hz,1H),7.44-7.29(m,6H),5.36(s,2H),3.40-3.10(m,9H),1.81-1.51(m,8H)。MS:m/z495.3[M+H] +。
Following compou nd synthesis method is similar to embodiment 3, and starting raw material is corresponding replacement 1-(3-carboxybenzyl) quinazoline-2,4 (1H, 3H)-diketone and corresponding substituted-piperazinyl.
Embodiment 163
The fluoro-1-of 5-(the fluoro-3-of 4-(4-(cyclopropyl carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.65(s,1H),7.65-7.57(m,1H),7.46-7.41(m,1H),7.38-7.35(m,1H),7.30-7.23(m,1H),7.04-6.98(m,2H),5.29(s,2H),3.75-3.15(m,8H),1.99-1.96(m,1H),0.72-0.69(m,4H)。MS:m/z469.5[M+H] +。
Embodiment 164
The chloro-1-of 6-(the fluoro-3-of 4-(4-benzoyl piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.85(s,1H),7.91(s,1H),7.68-7.62(m,1H),7.44-7.35(m,7H),7.28-7.22(m,2H),5.29(s,2H),3.64-3.21(m,8H)。MS:m/z521.5[M+H] +。
Embodiment 165
The fluoro-1-of 5-(3-(4-(cyclobutyl carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.66(s,1H),7.64-7.57(m,1H),7.43-7.36(m,2H),7.29-7.26(m,2H),7.04-6.98(m,2H),5.32(s,2H),3.56-3.00(m,9H),2.17-1.66(m,6H)。MS:m/z465.6[M+H] +。
Embodiment 166
The fluoro-1-of 5-(the fluoro-3-of 4-(4-(cyclobutyl carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.65(s,1H),7.65-7.57(m,1H),7.46-7.40(m,1H),7.36(d,J＝5.4Hz,1H),7.26(t,J＝9.0Hz,1H),7.04-6.99(m,2H),5.28(s,2H),3.55-3.09(m,9H),2.18-1.67(m,6H)。MS:m/z483.3[M+H] +。
Embodiment 167
The chloro-1-of 6-(the fluoro-3-of 6-(4-(cyclobutyl carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.87(s,1H),7.95(d,J＝2.4Hz,1H),7.69(dd,J＝8.9,2.6Hz,1H),7.42-7.30(m,2H),7.22-7.15(m,2H),5.33(s,2H),3.55-3.09(m,9H),2.14-1.72(m,6H)。MS:m/z499.3[M+H] +。
Embodiment 168
The chloro-1-of 5-(the fluoro-3-of 4-(4-(cyclobutyl carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.69(s,1H),7.55(t,J＝8.3Hz,1H),7.46-7.42(m,1H),7.37(d,J＝6.3Hz,1H),7.30-7.24(m,2H),7.18-7.13(m,1H),5.31(s,2H),3.56-3.11(m,9H),2.10-1.73(m,6H)。MS:m/z499.3[M+H] +。
Embodiment 169
The chloro-1-of 6-(the fluoro-3-of 4-(4-(cyclobutyl carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.88(s,1H),7.94(s,1H),7.70(dd,J＝9.0,2.7Hz,1H),7.46-7.42(m,1H),7.36(dd,J＝6.3,1.8Hz,1H),7.31-7.21(m,2H),5.30(s,2H),3.56-3.11(m,9H),2.50-1.73(m,6H)。MS:m/z499.3[M+H] +。
Embodiment 170
The chloro-1-of 5-(the fluoro-3-of 6-(4-(cyclobutyl carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.69(s,1H),7.57(t,J＝8.3Hz,1H),7.38-7.29(m,3H),7.20(d,J＝6.9Hz,1H),7.15(d,J＝8.7Hz,1H),5.35(s,2H),3.56-3.00(m,9H),2.12-1.74(m,6H)。MS:m/z499.4[M+H] +。
Embodiment 171
The chloro-1-of 5-(the fluoro-3-of 6-(4-(thiophene-2-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.72(s,1H),7.79(d,J＝5.1Hz,1H),7.54(t,J＝8.3Hz,1H),7.39-7.36(m,3H),7.25-7.22(m,2H),7.14-7.11(m,2H),5.35(s,2H),3.66-3.10(m,8H)。MS:m/z527.2[M+H] +。
Embodiment 172
The fluoro-1-of 5-(the fluoro-3-of 4-(4-(furans-2-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.67(s,1H),7.85(s,1H),7.66-7.58(m,1H),7.46-7.39(m,2H),7.29(t,J＝9.0Hz,1H),7.04-6.98(m,3H),6.64-6.63(m,1H),5.31(s,2H),3.73-3.70(m,4H),3.55-3.54(m,2H),3.23-3.22(m,2H)。MS:m/z495.3[M+H] +。
Embodiment 173
The chloro-1-of 5-(the fluoro-3-of 6-(4-(pyridine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.70(s,1H),8.12(dd,J＝4.8,1.2Hz,1H),7.62-7.52(m,2H),7.45-7.31(m,3H),7.22(d,J＝7.5Hz,1H),7.15(d,J＝8.4Hz,1H),6.75(d,J＝8.7Hz,1H),6.68-6.64(m,1H),5.36(s,2H),3.69-3.21(m,8H)。MS:m/z494.3[M+H] +。
Embodiment 174
The chloro-1-of 6-(the fluoro-3-of 6-(4-(pyridine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.86(s,1H),8.08(d,J＝3.9Hz,1H),7.92(d,J＝2.4Hz,1H),7.72(dd,J＝9.0,2.4Hz,1H),7.66-7.59(m,1H),7.44-7.32(m,2H),7.24(d,J＝9.0Hz,1H),7.20(d,J＝7.8Hz,1H),6.84(d,J＝7.5Hz,1H),6.70(t,J＝5.4Hz,1H),5.34(s,2H),3.69-3.21(m,8H)。MS:m/z494.3[M+H] +。
Embodiment 175
The chloro-1-of 6-(the fluoro-3-of 5-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.83(s,1H),8.36(d,J＝4.8Hz,2H),7.92(d,J＝2.4Hz,1H),7.70(d,J＝8.7Hz,1H),7.24-7.18(m,4H),6.64(t,J＝4.8Hz,1H),5.34(s,2H),3.69-3.21(m,8H)。MS:m/z495.3[M+H] +。
Embodiment 176
The fluoro-1-of 5-(the fluoro-3-of 5-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.63(s,1H),8.36(d,J＝4.8Hz,2H),7.66-7.61(m,1H),7.29(d,J＝9.3Hz,1H),7.19-7.16(m,2H),7.05-6.98(m,2H),6.65(t,J＝4.8Hz,1H),5.33(s,2H),3.80-3.20(m,8H)。MS:m/z479.3[M+H] +。
Embodiment 177
1-(3-(4-cyclopentyl-based piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.71(s,1H),8.02(dd,J＝8.0,1.4Hz,1H),7.63(t,J＝7.1Hz,1H),7.43-7.36(m,2H),7.26-7.21(m,4H),5.34(s,2H),3.65-3.30(m,9H),1.48-1.22(m,8H)。MS:m/z433.3[M+H] +。
Embodiment 178
The fluoro-1-of 6-(the fluoro-3-of 4-(4-(cyclopropyl carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.84(s,1H),7.74(dd,J＝8.1,3.0Hz,1H),7.56(t,J＝8.4Hz,1H),7.45-7.39(m,2H),7.31-7.25(m,2H),5.32(s,2H),3.54-3.16(m,8H),1.92(m,1H),0.73-0.70(m,4H)。MS:m/z469.3[M+H] +.。
Embodiment 179
The fluoro-1-of 6-(3-(4-(cyclobutyl carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.86(s,1H),7.75(dd,J＝8.3,2.9Hz,1H),7.56(t,J＝8.7Hz,1H),7.43-7.40(m,2H),7.31-7.26(m,3H),5.35(s,2H),3.52-3.31(m,9H),2.18-1.75(m,6H)。MS:m/z465.3[M+H] +。
Embodiment 180
The fluoro-1-of 6-(the fluoro-3-of 4-(4-(cyclobutyl carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.84(s,1H),7.74(d,J＝8.1Hz,1H),7.59-7.53(m,1H),7.46-7.44(m,1H),7.37(d,J＝5.7Hz,1H),7.31-7.25(m,2H),5.31(s,2H),3.57-3.11(m,9H),2.14-1.74(m,6H)。MS:m/z483.3[M+H] +。
Embodiment 181
The fluoro-1-of 6-(the fluoro-3-of 4-(4-benzoyl piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.84(s,1H),7.74(dd,J＝8.1,2.7Hz,1H),7.55-7.53(m,1H),7.46-7.42(m,7H),7.30-7.24(m,2H),5.31(s,2H),3.67-3.20(m,8H)。MS:m/z505.3[M+H] +。
Embodiment 182
The fluoro-1-of 5-(the fluoro-3-of 6-(4-(cyclobutyl carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.68(s,1H),7.66-7.59(m,1H),7.36-7.33(m,2H),7.18(d,J＝7.2Hz,1H),7.07-6.96(m,2H),5.32(s,2H),3.60-3.01(m,9H),2.11-1.73(m,6H)。MS:m/z483.4[M+H] +。
Embodiment 183
The fluoro-1-of 6-(the fluoro-3-of 6-(4-(cyclobutyl carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.84(s,1H),7.73(dd,J＝8.1,2.7Hz,1H),7.56(t,J＝8.4Hz,1H),7.36-7.30(m,2H),7.24-7.14(m,2H),5.34(s,2H),3.60-3.01(m,9H),2.14-1.72(m,6H)。MS:m/z483.3[M+H] +。
Embodiment 184
The fluoro-1-of 5-(the fluoro-3-of 6-(4-(furans-2-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.70(s,1H),7.86(s,1H),7.67-7.59(m,1H),7.39-7.36(m,2H),7.23(d,J＝7.2Hz,1H),7.05-6.97(m,3H),6.65-6.63(m,1H),5.34(s,2H),3.70-3.10(m,8H)。MS:m/z495.4[M+H] +。
Embodiment 185
The fluoro-1-of 6-(the fluoro-3-of 4-(4-(furans-2-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.84(s,1H),7.84(s,1H),7.74(dd,J＝8.4,3.0Hz,1H),7.59-7.53(m,1H),7.45-7.39(m,2H),7.32-7.26(m,2H),7.02(d,J＝3.3Hz,1H),6.63(dd,J＝3.3,1.8Hz,1H),5.32(s,2H),3.67-3.23(m,8H)。MS:m/z495.3[M+H] +。
Embodiment 186
The fluoro-1-of 6-(the fluoro-3-of 5-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.83(s,1H),8.39(d,J＝4.5Hz,2H),7.74(dd,J＝8.3,3.2Hz,1H),7.60-7.54(m,1H),7.33-7.29(m,2H),7.27-7.18(m,2H),6.67(t,J＝4.8Hz,1H),5.36(s,2H),3.80-3.35(m,8H)。MS:m/z479.4[M+H] +。
Embodiment 187
The fluoro-1-of 6-(the chloro-3-of 6-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.86(s,1H),8.37(d,J＝4.8Hz,2H),7.76-7.69(m,1H),7.65(d,J＝8.1Hz,1H),7.60-7.59(m,1H),7.38(dd,J＝8.3,1.7Hz,1H),7.13-7.09(m,2H),6.65(t,J＝4.7Hz,1H),5.32(s,2H),3.73-3.03(m,8H)。MS:m/z495.3[M+H] +。
Embodiment 188
The fluoro-1-of 6-(the fluoro-3-of 4-(4-(thiazol-2-yl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.82(s,1H),7.71(dd,J＝8.4,3.0Hz,1H),7.58-7.51(m,1H),7.43-7.38(m,2H),7.30-7.23(m,2H),7.17(d,J＝3.6Hz,1H),6.88(d,J＝3.6Hz,1H),5.30(s,2H),3.73-3.26(m,8H).MS:m/z484.3[M+H] +。
Embodiment 189
The fluoro-1-of 5-(the fluoro-3-of 4-(4-(thiazol-2-yl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.65(s,1H),7.65-7.57(m,1H),7.43-7.38(m,2H),7.27(t,J＝9.0Hz,1H),7.17(d,J＝3.6Hz,1H),7.04-6.98(m,2H),6.87(d,J＝3.6Hz,1H),5.29(s,2H),3.73-3.26(m,8H)。MS:m/z484.3[M+H] +。
Embodiment 190
1-(the fluoro-3-of 4-(4-(thiazol-2-yl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.70(s,1H),8.00(d,J＝8.1Hz,1H),7.64(t,J＝7.9Hz,1H),7.46-7.38(m,2H),7.30-7.22(m,3H),7.17(d,J＝3.6Hz,1H),6.87(d,J＝3.6Hz,1H),5.31(s,2H),3.79-3.23(m,8H)。MS:m/z466.3[M+H] +。
Embodiment 191
1-(3-(4-(cyclohexyl carboxyamide base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.67(s,1H),8.01(d,J＝7.8Hz,1H),7.63(t,J＝7.8Hz,1H),7.40-7.37(m,2H),7.30-7.22(m,4H),6.20(d,J＝4.0Hz,1H),5.33(s,2H),3.80-3.00(m,9H),1.80-1.00(m,10H)。MS:m/z490.4[M+H] +。
The hydrochloride of following compound at room temperature stirs 2.5 hours by corresponding compound and HCl/EA solution, and steaming desolventizes obtained.
Embodiment 192
1-(the fluoro-3-of 4-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-dione hydrochloride
1H?NMR(DMSO-d 6):11.71(s,1H),8.38(d,J＝4.8Hz,2H),8.00(d,J＝6.9Hz,1H),7.64(t,J＝7.8Hz,1H),7.46-7.39(m,2H),7.30-7.21(m,3H),6.67(t,J＝4.8Hz,1H),5.31(s,2H),3.81-3.78(m,2H),3.67-3.62(m,4H),3.24-3.20(m,2H)。MS:m/z461.2[M+H] +。
Embodiment 193
The fluoro-1-of 5-(the fluoro-3-of 4-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-dione hydrochloride
1H?NMR(DMSO-d 6):11.66(s,1H),8.41(d,J＝4.5Hz,2H),7.67-7.59(m,1H),7.47-7.39(m,2H),7.28(t,J＝4.5Hz,1H),7.06-6.99(m,2H),6.70(t,J＝4.8Hz,1H),5.31(s,2H),3.82-3.81(m,2H),3.69-3.64(m,4H),3.25-3.22(m,2H)。MS:m/z479.3[M+H] +。
Embodiment 194
1-(3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-dione hydrochloride
1H?NMR(DMSO-d 6):11.72(s,1H),8.37(d,J＝4.8Hz,2H),8.01(d,J＝6.9Hz,1H),7.64(t,J＝6.9Hz,1H),7.50-7.20(m,6H),6.66(t,J＝4.7Hz,1H),5.35(s,2H),4.10-3.20(m,8H)。MS:m/z443.3[M+H] +。
Embodiment 195
1-(3-((4-(pyridine-2-base) piperazine-1-base) methyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
A) 1-(3-(methylol) benzyl) quinazoline-2,4 (1H, 3H)-diketone: add 1-(3-methoxycarbonyl benzyl) quinazoline-2 in 20mL single port bottle, 4 (1H, 3H)-diketone (0.5g, 1.6mmol), 30mL THF and 10mL ethanol, then add NaBH 4(1.2g, 32mmol), under nitrogen protection, room temperature reaction 4 hours, reheats back flow reaction and spends the night.After raw material reaction is complete, first carefully extract sterilized amount NaBH with 2N dilute hydrochloric acid 4to releasing without gas, underpressure distillation removing ethanol and THF again, resistates 10mL water dilutes, extraction into ethyl acetate aqueous phase three times (10mL × 3), organic phase merging saturated common salt is washed once, obtain crude product with anhydrous sodium sulfate drying is concentrated, do not purify further, be directly used in next step reaction.
B) 1-(3-(methylsulphonic acid hydroxyl methoxycarbonyl) benzyl) quinazoline-2, 4 (1H, 3H)-diketone: under nitrogen protection, compound 1-(3-hydroxymethylbenzyl) quinazoline-2 is added successively in the 10mL single necked round bottom flask filling 2mL methylene dichloride, 4 (1H, 3H)-diketone crude product (0.1g, 0.35mmol), triethylamine (0.1g, 1.1mmol), under ice cooling, 4, MsCl (0.06g is dripped in reaction flask, 0.53mmol), at room temperature stir 2 hours, TLC detects, raw material reaction is complete, target product is had to generate, reaction solution is directly used in next step reaction.
C) 1-(3-((4-(pyridine-2-base) piperazine-1-base) methyl) benzyl) quinazoline-2; 4 (1H; 3H)-diketone: under nitrogen protection; 1-(pyridine-2-base) piperazine (57mg is added in above-mentioned reaction solution; dichloromethane solution 0.35mmol); reaction solution is heated to backflow, and stirring reaction spends the night.After raw material reaction is complete, underpressure distillation is except desolventizing again, resistates 2mL water dilutes, extraction into ethyl acetate aqueous phase three times (10mL × 3), organic phase merging saturated common salt is washed once, obtain crude product with anhydrous sodium sulfate drying is concentrated, thin layer preparative separation obtains desired product as white solid (5mg). 1H?NMR(DMSO-d 6):8.09(d,J＝3.3Hz,1H),8.02(d,J＝6.6Hz,1H),7.66-7.61(m,1H),7.54-7.48(m,1H),7.29-7.15(m,6H),6.78(d,J＝8.7Hz,1H),6.64-6.59(m,1H),5.32(s,2H),3.42-3.39(m,4H),2.40-2.37(m,4H)。MS:m/z428.3[M+H] +。
Following compou nd synthesis method is similar to embodiment 3, starting raw material is 1-(3-aminobenzyl) quinazoline-2,4 (1H, 3H)-diketone is (by quinazoline-2,4 (1H, 3H)-diketone and 1-(brooethyl)-3-oil of mirbane application class be similar to the method for embodiment 1 and reduction obtained) and corresponding substituted acetic acid.
Embodiment 196
1-(3-(naphthalene-2-base) Acetamidobenzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.72(brs,1H),10.23(s,1H),8.10-7.99(m,1H),7.90-7.76(m,4H),7.62-7.56(m,2H),7.46-7.38(m,4H),7.26-7.16(m,3H),7.05-6.90(m,1H),5.25(s,2H),3.75(s,2H)。MS:m/z436.4[M+H] +。
Embodiment 197
1-(3-(3,4-Dimethoxyphenyl) Acetamidobenzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.70(brs,1H),10.03(s,1H),8.01(dd,J＝7.8,1.2Hz,1H),7.65-7.55(m,2H),7.34(s,1H),7.27-7.17(m,3H),6.98(d,J＝7.8Hz,1H),6.83-6.77(m,3H),5.26(s,2H),3.69(s,6H),3.47(s,2H)。MS:m/z446.3[M+H] +。
Embodiment 198
1-(3-([1,2,4] triazole [4,3-a] pyridine-6-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
A) 1-(3-(N-methoxy-. N-methyl formamyl) benzyl) quinazoline-2; 4 (1H; 3H)-diketone: under nitrogen protection; compound 1-(3-carboxybenzyl) quinazoline-2 is added successively in the 50mL single necked round bottom flask filling 20mL methylene dichloride; 4 (1H; 3H)-diketone (0.5g; 1.68mmol), HATU (0.96g; 2.5mmol) with DIPEA (0.9g; 7.0mmol), N; O-dimethyl hydroxyl amine hydrochlorate (0.2g, 2.0mmol), reactant is heated to 40 DEG C of stirrings and spends the night.After TLC follows the tracks of and reacts completely, reaction solution concentrates, dilute with water, extraction into ethyl acetate aqueous phase three times (10mL × 3), organic phase merging water and saturated common salt washing, crude product is obtained with anhydrous sodium sulfate drying is concentrated, target product (0.4g, 70%) is obtained through column chromatography (ethyl acetate).
B) 1-(3-([1, 2, 4] triazole [4, 3-a] pyridine-6-carbonyl) benzyl) quinazoline-2, 4 (1H, 3H)-diketone: under nitrogen protection, 6-bromo-[1 is added successively to in three mouthfuls of round-bottomed flasks of low-reading thermometer, 2, 4] triazole [4, 3-a] pyridine (35mg, 0.18mmol), anhydrous THF (1mL), dry ice acetone bath makes reaction solution be down to less than-65 DEG C, n-BuLi (0.15mL is slowly dripped under stirring, 0.38mmol), drip off maintenance temperature of reaction-65 DEG C, stir 3 hours, 1-(3-(N-methoxyl group-N-formamido-) benzyl) quinazoline-2 is dripped again in reaction flask, 4 (1H, 3H)-diketone (50mg, 0.15mmol) anhydrous THF (1mL) solution, drip off maintenance temperature of reaction-65 DEG C, stir 4 hours, slowly be raised to 0 DEG C to having reacted, reaction solution pours saturated NH into 4in the Cl aqueous solution, extraction is gone out, extraction into ethyl acetate three times (10mL × 3), organic phase merging saturated common salt is washed once, obtains crude product with anhydrous sodium sulfate drying is concentrated, thin layer preparative separation obtains desired product as white solid (6.5mg, 11%). 1H?NMR(CD 3OD+CDCl 3):9.42(d,J＝7.2Hz,1H),8.41-8.39(m,2H),8.10(d,J＝7.2Hz,1H),7.95(d,J＝9.0Hz,1H),7.58-7.45(m,4H),7.18-7.11(m,3H),5.38(s,2H)。MS:m/z398.2[M+H] +。
Following compou nd synthesis method is similar to embodiment 3, starting raw material is corresponding replacement 1-(3-carboxybenzyl) quinazoline-2,4 (1H, 3H)-diketone or 1-((2-carboxyl pyridine-6-base) methyl) quinazoline-2,4 (1H, 3H)-diketone and corresponding replacement amine.
Embodiment 199
The fluoro-1-of 6-((2-(4-(pyrimidine-2-base) piperazine-1-carbonyl) pyridine-6-base) methyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.84(s,1H),8.39(d,J＝4.8Hz,2H),7.94(t,J＝7.8Hz,1H),7.72-7.70(m,1H),7.57-7.53(m,3H),7.34-7.30(m,1H),6.67(t,J＝4.8Hz,1H),5.46(s,2H),3.73-3.63(m,4H),3.42-3.32(m,4H)。MS:m/z462.5[M+H] +。
Embodiment 200
The fluoro-1-of 5-(the fluoro-3-of 4-(4-methoxYbenzylamino formyl radical) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.70(s,1H),8.79(t,J＝5.3Hz,1H),7.66-7.57(m,2H),7.46-7.41(m,1H),7.27-7.20(m,3H),7.08-6.99(m,2H),6.90-6.87(m,2H),5.30(s,2H),4.37(d,J＝6.0Hz,2H),3.73(s,3H)。MS:m/z452.2[M+H] +。
Embodiment 201
The fluoro-1-of 5-(the fluoro-3-of 4-(3-chlorobenzylcarbamoyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.70(s,1H),9.01(t,J＝5.1Hz,1H),7.75-7.68(m,2H),7.57-7.52(m,1H),7.48-7.32(m,5H),7.18-7.08(m,2H),5.31(s,2H),4.45(d,J＝5.7Hz,2H)。MS:m/z456.1[M+H] +。
Embodiment 202
The fluoro-1-of 5-(the fluoro-3-of 4-(carbamovl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.70(s,1H),8.87(t,J＝5.1Hz,1H),7.67-7.59(m,2H),7.47-7.42(m,1H),7.36-7.22(m,6H),7.09-6.99(m,2H),5.31(s,2H),4.45(d,J＝6.0Hz,1H)。MS:m/z422.3[M+H] +。
Embodiment 203
5-methoxyl group-1-(3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.32(s,1H),8.38(d,J＝4.8Hz,2H),7.53(t,J＝8.4Hz,1H),7.44-7.29(m,4H),6.85(d,J＝8.4Hz,1H),6.75(d,J＝8.4Hz,1H),6.67(t,J＝4.8Hz,1H),5.33(s,2H),3.84(s,3H),3.79-3.42(m,8H)。MS:m/z473.3[M+H] +。
Embodiment 204
6-methoxyl group-1-(3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.71(s,1H),8.38(d,J＝4.8Hz,2H),7.47-7.40(m,3H),7.34-7.26(m,3H),7.20(d,J＝9.3Hz,1H),6.67(t,J＝4.8Hz,1H),5.35(s,2H),3.80(s,3H),3.63-3.46(m,8H)。MS:m/z473.3[M+H] +。
Embodiment 205
The fluoro-1-of 5-(the fluoro-3-of 4-(5-bromo pyrimi piperidine-2-carbamoylamino) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.73(s,1H),10.27(s,1H),9.43(s,1H),8.50(s,2H),7.68-7.52(m,3H),7.28(t,J＝9.3Hz,1H),7.11-7.00(m,2H),5.33(s,2H)。MS:m/z503.0[M+H] +。
Embodiment 206
7-Trifluoromethyl-1-(3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.96(s,1H),8.36(d,J＝4.8Hz,2H),8.19(d,J＝8.1Hz,1H),7.55(d,J＝8.4Hz,1H),7.47(s,1H),7.43-7.39(m,3H),7.33-7.30(m,1H),6.65(t,J＝4.7Hz,1H),5.44(s,2H),3.59-3.46(m,8H)。MS:m/z511.2[M+H] +。
Embodiment 207
6,7-ethylene Oxy-1-(3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.55(s,1H),8.39(d,J＝4.8Hz,2H),7.44-7.34(m,5H),6.75(s,1H),6.67(t,J＝4.8Hz,1H),5.29(s,2H),4.32-4.27(m,4H),3.88-3.56(m,8H)。MS:m/z501.2[M+H] +。
Embodiment 208
The fluoro-1-of 5-(6-methoxyl group-3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.65(s,1H),8.37(d,J＝4.8Hz,2H),7.67-7.60(m,1H),7.39(dd,J＝8.4,1.8Hz,1H),7.16(d,J＝8.4Hz,1H),7.07-6.98(m,2H),6.87(d,J＝8.4Hz,1H),6.65(t,J＝4.7Hz,1H),5.20(s,2H),3.95(s,3H),3.82-3.16(m,8H)。MS:m/z491.2[M+H] +。
Embodiment 209
7-methoxyl group-1-(3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.54(s,1H),8.37(d,J＝4.8Hz,2H),7.92(d,J＝8.7Hz,1H),7.42-7.30(m,4H),6.84(dd,J＝8.9,2.3Hz,1H),6.68-6.63(m,2H),5.34(s,2H),3.76(s,3H),3.71-3.51(m,8H)。MS:m/z473.3[M+H] +。
Embodiment 210
The fluoro-1-of 5-(the fluoro-3-of 4-(4-(tetrahydrofuran (THF)-2-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.67(s,1H),7.66-7.59(m,1H),7.47-7.42(m,1H),7.38(d,J＝6.0Hz,1H),7.28(t,J＝9.0Hz,1H),7.10-6.95(m,2H),5.30(s,2H),4.75-4.50(m,1H),3.85-3.45(m,8H),3.25-3.00(m,2H),2.15-1.70(m,4H)。MS:m/z499.3[M+H] +。
Embodiment 211
The fluoro-1-of 5-(4-nitro-3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.71(s,1H),8.40(d,J＝3.9Hz,2H),8.17(d,J＝8.7Hz,1H),7.63-7.57(m,3H),7.07-6.94(m,2H),6.69(t,J＝4.4Hz,1H),5.45(s,2H),3.85-3.84(m,2H),3.70-3.69(m,2H),3.61-3.59(m,2H),3.21-3.18(m,2H)。MS:m/z506.2[M+H] +。
Embodiment 212
The fluoro-1-of 5-(the fluoro-3-of 4-(4-cyclohexylpiperazin-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.68(s,1H),7.66-7.58(m,1H),7.45-7.40(m,1H),7.30-7.23(m,2H),7.06-6.99(m,2H),5.30(s,2H),3.56-3.07(m,8H),2.33-2.25(m,1H),1.72-1.04(m,10H)。MS:m/z483.5[M+H] +。
Embodiment 213
The fluoro-1-of 5-(the fluoro-3-of 4-(4-phenylpiperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.68(s,1H),7.67-7.60(m,1H),7.48-7.38(m,2H),7.32-7.20(m,3H),7.07-7.00(m,2H),6.94-6.91(m,2H),6.82(t,J＝7.2Hz,1H),5.31(s,2H),3.85-3.65(m,2H),3.45-3.10(m,4H),3.10-2.90(m,2H)。MS:m/z477.4[M+H] +。
Embodiment 214
The fluoro-1-of 5-(the fluoro-3-of 4-(4-Phenylpiperidine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.68(s,1H),7.62-7.56(m,1H),7.45-7.37(m,2H),7.33-7.18(m,6H),7.04-6.93(m,2H),5.45-5.15(m,2H),4.70-4.55(m,1H),3.50-3.05(m,2H),2.95-2.65(m,2H),1.80-1.20(m,4H)。MS:m/z476.4[M+H] +。
Embodiment 215
The fluoro-1-of 5-(the bromo-3-of 4-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.67(s,1H),8.39(d,J＝4.8Hz,2H),7.66-7.58(m,2H),7.37(d,J＝1.8Hz,1H),7.30(dd,J＝8.4,2.1Hz,1H),7.06-6.97(m,2H),6.68(t,J＝4.8Hz,1H),5.37-5.22(m,2H),3.82-3.11(m,8H)。MS:m/z539.3[M+H] +。
Embodiment 216
6,7-methylenedioxy-1-(3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.64(s,1H),8.39(d,J＝4.5Hz,2H),7.44-7.32(m,5H),6.95(s,1H),6.67(t,J＝4.4Hz,1H),6.14(s,2H),5.33(s,2H),3.81-3.65(m,8H)。MS:m/z487.2[M+H] +。
Embodiment 217
The fluoro-1-of 5-(the fluoro-3-of 4-(4-(cyclohexyl methyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.70(s,1H),7.66-7.58(m,1H),7.44-7.40(m,1H),7.32-7.23(m,2H),7.05-6.99(m,2H),5.30(s,2H),3.70-3.50(m,2H),3.20-3.00(m,2H),2.38-2.28(m,2H),2.20-2.10(m,2H),2.05(d,J＝6.6Hz,2H),1.73-1.63(m,5H),1.45-1.39(m,1H),1.30-1.00(m,3H),0.90-0.70(m,2H)。MS:m/z497.3[M+H] +。
Embodiment 218
The fluoro-1-of 8-(3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1H?NMR(DMSO-d 6):11.93(s,1H),8.38(d,J＝4.8Hz,2H),7.89(d,J＝7.8Hz,1H),7.60-7.52(m,1H),7.45-7.22(m,5H),6.66(t,J＝4.8Hz,1H),5.40(s,2H),3.90-3.20(m,8H)。MS:m/z461.2[M+H] +。
Embodiment 219
6-amino-1-(3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
To 6-nitro-1-(3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, iron powder (33.5mg0.60mmol) and saturated NH is added in EtOH (10mL) solution of 3H)-diketone (50mg, 0.10mmol) 4cl solution (0.2mL), at N 2under protection, heated overnight at reflux.Be cooled to room temperature, filter, filtrate is concentrated is separated to obtain yellow solid target product (10.79mg, 23.6%) through thin plate chromatography (DCM:MeOH=50:3). 1H?NMR(DMSO-d 6):11.46(s,1H),8.39(d,J＝4.8Hz,2H),7.42-7.31(m,4H),7.20(d,J＝2.7Hz,1H),7.00(d,J＝8.7Hz,1H),6.89(dd,J＝8.7,2.7Hz,1H),6.67(t,J＝4.8Hz,1H),5.26(s,4H),3.81-3.68(m,8H)。MS:m/z458.3[M+H] +。
Embodiment 220
1-(2-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
Synthetic method is similar to embodiment 3, starting raw material is 1-(2-carboxybenzyl) quinazoline-2,4 (1H, (synthetic method is similar to implementation column 1 and 2 to 3H)-diketone, starting raw material is quinazoline-2,4 (1H, 3H)-diketone and 2-(brooethyl) methyl benzoate) and 2-(piperazine-1-base) pyrimidine. 1H?NMR(DMSO-d 6):11.76(s,1H),8.40(d,J＝4.8Hz,2H),8.03-8.00(m,1H),7.70-7.50(m,1H),7.35-7.00(m,6H),6.68(t,J＝4.8Hz,1H),5.25(s,2H),4.10-3.60(m,8H)。MS:m/z443.2[M+H] +。
Embodiment 221
1-(3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) phenyl) quinazoline-2,4 (1H, 3H)-diketone
A) 3-(3-(2-Bromophenacyl) urea groups) methyl benzoate: to 2-bromobenzene acid amides (2.0g, in DCM (30mL) solution 10.0mmol), slowly add oxalyl chloride (1.65g, 13.0mmol), back flow reaction 23 hours, reaction end adds gavaculine methyl esters (1.66g, 11.0mmol), back flow reaction 20 minutes.After reacting completely, be poured into water by reaction solution, filtered by precipitate, gained solid ethyl alcohol recrystallization obtains crude product (1.80g, 48%), is directly used in next step without purification.
B) 1-(3-methoxycarbonyl-phenyl) quinazoline-2; 4 (1H; 3H)-diketone: add 3-(3-(2-Bromophenacyl) urea groups) methyl benzoate (1.8g in 100mL single port bottle; 4.8mmol); potassium tert.-butoxide (2.69g; 24mmol) with DMF (20mL); react 2.25 hours under 70-80 DEG C of nitrogen protection; reaction terminates rear dilute with water; filtration draws crude product; desired product as white solid (0.34g, 24%) is obtained through column chromatography (ethyl acetate).MS:m/z297[M+1] +。
C) 1-(3-carboxyl phenyl) quinazoline-2,4 (1H, 3H)-diketone: the synthetic method that application class is similar to described embodiment 2 obtains, starting raw material is 1-(3-methoxycarbonyl-phenyl) quinazoline-2,4 (1H, 3H)-diketone and sodium hydroxide, be separated and obtain white solid.MS:m/z283[M+H] +。
D) 1-(3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) phenyl) quinazoline-2,4 (1H, 3H)-diketone: the synthetic method that application class is similar to described implementation column 3 obtains, starting raw material is 1-(3-carboxyl phenyl) quinazoline-2,4 (1H, 3H)-diketone and 2-(piperazine-1-base) pyrimidine, be separated and obtain white solid. 1H?NMR(DMSO-d 6):11.72(s,1H),8.36(d,J＝4.8Hz,2H),8.02(d,J＝6.6Hz,1H),7.69-7.55(m,5H),7.25(t,J＝7.5Hz,1H),6.65(t,J＝4.7Hz,1H),6.48(d,J＝8.4Hz,1H),3.80-3.20(m,8H)。MS:m/z429.1[M+H] +。
Embodiment 222
The chloro-1-of 8-(3-methoxycarbonyl benzyl) quinazoline-2,4 (1H, 3H)-diketone and the chloro-3-of 8-(3-methoxycarbonyl benzyl) quinazoline-2,4 (1H, 3H)-diketone
By 8-chloro-quinazoline-2,4 (1H, 3H)-diketone (5.1g, 25.9mmol), hexamethyldisilazane (HMDS, 10.4g, 64.9mmol) and toluene 50mL join in 100mL bis-mouthfuls of bottles, add the vitriol oil (0.25g under stirring, 2.6mmol), back flow reaction 8 hours.Underpressure distillation removing toluene and excessive HMDS.3-bromomethyl-benzoic acid methyl ester (5.9g, 25.9mmol) and DMF (1mL) are joined in residue obtained above, is warming up to 160 DEG C of reactions 3 hours.Add dioxane (6mL) after being cooled to 100 DEG C, then be cooled to 70 DEG C and add methyl alcohol (10mL), stir 0.5 hour.After being cooled to 5 DEG C, there is solid to separate out, filter.Filter cake uses water (20mL) and methyl alcohol (10mL) washing respectively, dries, obtains gray solid target product (2.6g, 29.1%).MS:m/z477.1[M+H] +。Filtrate concentrates, the chloro-1-of another target compound 8-(3-methoxycarbonyl benzyl) quinazoline-2 is obtained through thin plate chromatography (PE:EA=1:1) purifying, 4 (1H, 3H)-diketone is yellow solid (0.2g, 1.8%).MS:m/z477.1[M+H] +。
Embodiment 223
The chloro-3-of 8-(3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
Synthetic method is similar to embodiment 3, starting raw material is the chloro-3-of 8-(3-carboxybenzyl) quinazoline-2,4 (1H, (synthetic method is similar to embodiment 2 to 3H)-diketone, starting raw material is the chloro-3-of 8-(3-methoxycarbonyl benzyl) quinazoline-2,4 (1H, 3H)-diketone and NaOH) and 2-(piperazine-1-base) pyrimidine. 1H?NMR(DMSO-d 6):11.15(s,1H),8.38(d,J＝4.8Hz,2H),7.95(d,J＝7.8Hz,1H),7.82(d,J＝7.5Hz,1H),7.50-7.30(m,4H),7.23(t,J＝7.8Hz,1H),6.67(t,J＝4.8Hz,1H),5.14(s,2H),3.90-3.55(m,8H)。MS:m/z477.1[M+H] +。
Embodiment 224
The chloro-1-of 8-(3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
Synthetic method is similar to embodiment 3, starting raw material is the chloro-1-of 8-(3-carboxybenzyl) quinazoline-2,4 (1H, (synthetic method is similar to embodiment 2 to 3H)-diketone, starting raw material is the chloro-1-of 8-(3-methoxycarbonyl benzyl) quinazoline-2,4 (1H, 3H)-diketone and NaOH) and 2-(piperazine-1-base) pyrimidine. 1H?NMR(DMSO-d 6):11.94(s,1H),8.38(d,J＝4.8Hz,2H),8.05(d,J＝6.6Hz,1H),7.77(d,J＝6.6Hz,1H),7.50-7.20(m,5H),6.66(t,J＝4.8Hz,1H),5.53(s,2H),3.90-3.50(m,8H)。MS:m/z477.1[M+H] +。
Embodiment 225
8-methyl-3-(3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
Synthetic method is similar to embodiment 3, starting raw material is 8-methyl-3-(3-carboxybenzyl) quinazoline-2,4 (1H, (synthetic method is similar to embodiment 222 and 223 to 3H)-diketone, starting raw material is 8-methylquinazolin-2,4 (1H, 3H)-diketone and 3-(brooethyl) methyl benzoate) and 2-(piperazine-1-base) pyrimidine. 1H?NMR(DMSO-d 6):10.81(s,1H),8.36(d,J＝4.5Hz,2H),7.83(d,J＝7.5Hz,1H),7.52(d,J＝7.2Hz,1H),7.45-7.30(m,4H),7.13(t,J＝7.7Hz,1H),6.67(t,J＝4.7Hz,1H),5.15(s,2H),3.92-3.46(m,8H),2.36(s,3H)。MS:m/z457.3[M+H] +。
Embodiment 226
8-methyl isophthalic acid-(3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
A) 8-methyl isophthalic acid H-benzo [d] [1,3] oxazines-2,4-diketone: by 2-amino-3-tolyl acid (5.03g, 33.3mmol) be dissolved in 50mL tetrahydrofuran (THF), triphosgene (9.92g, 33.4mmol) is added, stirred at ambient temperature 15 minutes in this solution.Filter, filter cake water and tetrahydrofuran (THF) washing, dry desired product as white solid (5.10g, 86.4%).MS:m/z178.1[M+H] +。
B) 2-Amino-N-tert-butyl-3-methyl benzamide: add 8-methyl isophthalic acid H-benzo [d] [1 in 100mL single port bottle, 3] oxazines-2,4-diketone (3.89g, 22.0mmol), TERTIARY BUTYL AMINE (2.55mL, 24.1mmol), DMAP (0.27g, 2.2mmol) with DMF (30mL), stirred overnight at room temperature.Be poured into water by reaction solution, have solid to separate out, filter, filter cake washes with water, dry white solid target crude product (1.68g, 37.1%).MS:m/z207.2[M+H] +。
C) the 3-tertiary butyl-8-methylquinazolin-2,4 (1H, 3H) diketone: add 2-Amino-N-tert-butyl-3-methyl benzamide (0.52g in 100mL single port bottle, 2.5mmol), N, N'-carbonyl dimidazoles (CDI, 0.85g, 5.2mmol) and THF (20mL), be warming up to back flow reaction and spend the night.After being down to room temperature, be poured into water by reaction solution, have solid to separate out, filter, filter cake washes with water, dry desired product as white solid (0.25g, 42.6%). 1H?NMR(DMSO-d 6):10.33(s,1H),7.68(d,J＝7.8Hz,1H),7.41(d,J＝7.2Hz,1H),7.04(t,J＝7.6Hz,1H),2.31(s,3H),1.66(s,9H)。
D) the 3-tertiary butyl-8-methyl isophthalic acid-(3-methoxycarbonyl benzyl) quinazoline-2,4 (1H, 3H)-diketone: add the 3-tertiary butyl-8-methylquinazolin-2,4 (1H, 3H)-diketone (1.00g in 100mL single port bottle, 4.3mmol), 3-bromomethyl-benzoic acid methyl ester (0.99g, 4.3mmol), sodium methylate (0.28g, 5.2mmol) with DMF (15mL), be warming up to 50 DEG C of reactions and spend the night.After reaction terminates, reaction solution is directly used in next step reaction and does not do any process.MS:m/z403.2[M+Na] +。
E) 8-methyl isophthalic acid-(3-carboxybenzyl) quinazoline-2,4 (1H, 3H)-diketone: add 40mL6N hydrochloric acid soln in above-mentioned reaction solution, is warming up to 80 DEG C of reactions 6 hours.After being down to room temperature, be poured into water by reaction solution, have solid to separate out, filter, filter cake washes with water, dry yellow solid target product (0.27g, 20.1%).MS:m/z311.1[M+H] +。
F) 8-methyl isophthalic acid-(3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone: synthetic method is similar to embodiment 3, starting raw material is 8-methyl isophthalic acid-(3-carboxybenzyl) quinazoline-2,4 (1H, 3H)-diketone and 2-(piperazine-1-base) pyrimidine. 1H?NMR(DMSO-d 6):11.70(s,1H),8.38(d,J＝4.8Hz,2H),7.92(d,J＝6.9Hz,1H),7.50-7.26(m,5H),7.17(t,J＝7.5Hz,1H),6.65(t,J＝4.8Hz,1H),5.35(s,2H),3.85-3.15(m,8H),2.35(s,3H)。MS:m/z457.2[M+H] +。
Embodiment 227
8-methoxyl group-1-(3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
Synthetic method is similar to embodiment 226, and starting raw material is 2-amino-3-methoxybenzoic acid. 1H?NMR(DMSO-d 6):11.76(s,1H),8.38(d,J＝4.8Hz,2H),7.65(d,J＝6.6Hz,1H),7.45-7.17(m,6H),6.67(t,J＝4.7Hz,1H),5.51(s,2H),3.80-3.64(m,8H),3.56(s,3H)。MS:m/z473.2[M+H] +。
Embodiment 228
3-(3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
A) 3-(3-methoxycarbonyl benzyl) quinazoline-2,4 (1H, 3H)-diketone: quinazoline-2,4 (1H, 3H)-diketone (2.5g, 15.4mmol), 3-(brooethyl) methyl benzoate (3.56g, 15.4mmol) and K 2cO 3dMF (30mL) suspension liquid of (4.26g, 30.8mmol) at room temperature stirs and spends the night.In reaction solution, add 150mL water, have solid to separate out, filter, filter cake is through column chromatography (CH 2cl 2: MeOH=200:1) purifying obtains desired product as white solid (0.87g, 18.2%). 1H?NMR(DMSO-d 6):11.51(s,1H),8.00-7.90(m,2H),7.84(d,J＝7.5Hz,1H),7.75-7.55(m,2H),7.47(t,J＝7.8Hz,1H),7.30-7.15(m,2H),5.14(s,2H),3.83(s,3H)。MS:m/z311.2[M+H] +。
B) 3-(3-carboxybenzyl) quinazoline-2,4 (1H, 3H)-diketone: synthetic method is similar to embodiment 2, starting raw material is 3-(3-methoxycarbonyl benzyl) quinazoline-2,4 (1H, 3H)-diketone.MS:m/z297.2[M+H] +。
C) 3-(3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone: synthetic method is similar to embodiment 3, starting raw material is 3-(3-carboxybenzyl) quinazoline-2,4 (1H, 3H)-diketone and 2-(piperazine-1-base) pyrimidine. 1H?NMR(DMSO-d 6):11.55(s,1H),8.36(d,J＝4.8Hz,2H),7.93(d,J＝6.9Hz,1H),7.66(t,J＝7.1Hz,1H),7.45-7.26(m,4H),7.25-7.12(m,2H),6.65(t,J＝4.7Hz,1H),5.11(s,2H),3.90-3.20(m,8H)。MS:m/z443.3[M+H] +。
Embodiment 229
1-(3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) styroyl) quinazoline-2,4 (1H, 3H)-diketone
Synthetic method is similar to embodiment 3, starting raw material is 1-(3-carboxyl styrene base) quinazoline-2,4 (1H, (synthetic method is similar to embodiment 1 and 2 to 3H)-diketone, starting raw material is quinazoline-2,4 (1H, 3H)-diketone and 3-(2-bromotrifluoromethane) methyl benzoate) and 2-(piperazine-1-base) pyrimidine. 1H?NMR(DMSO-d 6):11.54(s,1H),8.37(d,J＝4.8Hz,2H),7.78(dd,J＝7.8,1.5Hz,1H),7.73(t,J＝6.9Hz,1H),7.52(d,J＝7.2Hz,1H),7.35-7.22(m,5H),6.66(t,J＝4.7Hz,1H),4.28(t,J＝7.5Hz,2H),3.80-3.20(m,8H),2.95(t,J＝7.4Hz,1H)。MS:m/z457.4[M+H] +。
Embodiment 230
8-hydroxyl-1-(3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
8-methoxyl group-1-(3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2 is added in 100mL single port bottle, 4 (1H, 3H)-diketone (60mg, 0.13mmol) with 25mL methylene dichloride, after being down to-70 DEG C, slowly add boron tribromide-dichloromethane solution (4N, 10mL, 40mmol), gained reaction solution at room temperature stirs and spends the night.Under cryosel bath cooling conditions, in reaction solution, slowly dropwise add methyl alcohol (10mL), then add ammonium chloride saturated solution, pH is adjusted to weakly acidic pH.With methylene dichloride (50mL × 2) extraction, concentrate after organic layer drying, obtain desired product as white solid (7.64mg, 13.1%) through column chromatography (DCM:MeOH=20:1). 1H?NMR(DMSO-d 6):11.64(s,1H),10.34(s,1H),8.36(d,J＝4.8Hz,2H),7.51(dd,J＝6.8,2.6Hz,1H),7.39-7.34(m,1H),7.27-7.23(m,3H),7.10-7.03(m,2H),6.65(t,J＝4.7Hz,1H),5.63(s,2H),3.85-3.53(m,8H)。MS:m/z459.4[M+H] +。
Embodiment 231
The active MTT detection method of application cell measures 1-(3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone and its resemblance are to the synergistic enhancing effect of the T suppression cell accretion of methyl methylsulfonate (MMS)
The active MTT detection method of application cell, human colon cancer cell SW620 is used to measure PARP inhibitor to DNA damage kind anti-cancer drugs thing, the such as synergistic enhancing effect of the T suppression cell accretion of methyl methylsulfonate (MMS).In brief, human colon cancer cell SW620 is used to the cell growth inhibiting effect weighing DNA alkylating agent cancer therapy drug MMS.The MMS concentration used in the detection carefully will be titrated to a level, makes the restraining effect of MMS cell growth minimum.And with this understanding, can Sensitive Detection 1-(arylmethyl) quinazoline-2,4 (1H, 3H)-diketone to the reinforcing effect of the cell growth inhibiting effect of MMS.RPMI1640 (Gibco) substratum is used to cultivate SW620 cell containing 10%FBS (Hyclone).Experiment first day, with 4000 cells/well by cell seeding to 96 porocyte culture plate, is placed in 5%CO 2the inherent 37 DEG C of overnight incubation of incubator.Second day removing cell culture fluid, every hole adds the fresh culture of 180 μ L containing MMS1.5 μ g/mL.Then positive compound (AZD2281 and ABT-888) or testing compound that 20 μ L contain 10 times of concentration is added.Positive compound and testing compound carry out continuous series dilution by 1:3 and 1:10 DMSO.The diluent of ten times of concentration is mixed with by 10 μ L DMSO diluents and 90 μ L fresh cultures and forms.In nutrient solution, the ultimate density of DMSO is 1%.Then cell puts back to 5%CO 25 days (120 hours) cultivated by inherent 37 DEG C of incubator.Take out 96 porocyte culture plates afterwards in every hole, to add 20 μ L MTT solution hatch 4 hours at 37 DEG C.Removing nutrient solution, adds 100 μ L DMSO, shake well 10 minutes in every hole.96 orifice plates are put into microplate reader, and 520/690nm carries out reading.The Prism5 software of data analysis GraphPad company carries out.Data are mapped to the difference of 520/690nm reading by with the compound concentration of logarithmetics, and carry out curve equation model with following equations and draw IC 50value, Y (absorption value)=minimal absorption value+(obtained the maximum absorption-minimal absorption value)/(1+10^ (LogC-LogIC50)), C is compound concentration.
The IC calculated 50value refers to that 1-(arylmethyl) quinazoline-2,4 (1H, 3H)-diketone, to the synergistic enhancing effect of the T suppression cell accretion of methyl methylsulfonate (MMS), gathers in table 1 in MTT cell viability detects.
Form 1. replaces the synergistic enhancing effect (IC of 1-(arylmethyl) quinazoline-2,4 (1H, 3H)-diketone to the T suppression cell accretion of MMS 50value)
Embodiment 1 2 3 4 5 6 7 8
IC 50(nM) >10000 >10000 90 12 5356 7026 5269 112
Embodiment 9 10 11 12 13 14 15 16
IC 50(nM) 500 439 618 533 727 102 666 7259
Embodiment 17 18 19 20 21 22 23 24
IC 50(nM) >10000 >10000 >10000 391 >10000 >10000 8.2 26
Embodiment 25 26 27 28 29 30 31 32
IC 50(nM) 9.8 149 83 >10000 >10000 119 2595 106
Embodiment 33 34 35 36 37 38 39 40
IC 50(nM) 130 294 265 >10000 >10000 >10000 604 182
Embodiment 41 42 43 44 45 46 47 48
IC 50(nM) 11 78 51 6.8 34 21 54 56
Embodiment 49 50 51 52 53 54 55 56
IC 50(nM) 32 37 33 55 59 217 89 30
Embodiment 57 58 59 60 61 62 63 64
IC 50(nM) 46 171 >10000 >10000 61 816 50 177
Embodiment 65 66 67 68 69 70 71 72
IC 50(nM) 417 991 2054 673 352 136 70 80
Embodiment 73 74 75 76 77 78 79 80
IC 50(nM) 3379 >10000 2661 ND 2964 269 5543 >10000
Embodiment 81 82 83 84 85 86 87 88
IC 50(nM) 99 459 72 52 25 86 35 137
Embodiment 89 90 91 92 93 94 95 96
IC 50(nM) ND >10000 >10000 >10000 >10000 >10000 >10000 >10000
Embodiment 97 98 99 100 101 102 103 104
IC 50(nM) >10000 >10000 >10000 202 117 87 45 8.3
Embodiment 105 106 107 108 109 110 111 112
IC 50(nM) 7.9 105 6.3 78 48 72 27 14
Embodiment 113 114 115 116 117 118 119 120
IC 50(nM) 9.6 51 19 48 5.1 0.82 0.72 42
Embodiment 121 122 123 124 125 126 127 128
IC 50(nM) 4.5 Td 15 9.9 6.7 18 13 37
Embodiment 129 130 131 132 133 134 135 136
IC 50(nM) 18 15 17 4.1 4.1 5.8 6.8 7.1
Embodiment 137 138 139 140 141 142 143 144
IC 50(nM) 7.0 351 16 37 12 22 15 2.8
Embodiment 145 146 147 148 149 150 151 152
IC 50(nM) 12 3.4 2.7 2.1 14 25 18 13
Embodiment 153 154 155 156 157 158 159 160
IC 50(nM) 9.2 7.3 23 28 18 7.8 648 394
Embodiment 161 162 163 164 165 166 167 168
IC 50(nM) 506 1193 28 6.2 49 4.0 5.2 15
Embodiment 169 170 171 172 173 174 175 176
IC 50(nM) 3.4 120 70 9.5 228 94 16 15
Embodiment 177 178 179 180 181 182 183 184
IC 50(nM) >10000 7.9 12 3.1 4.9 16 13 62
Embodiment 185 186 187 188 189 190 191 192
IC 50(nM) 6.7 24 27 7.8 10 21 192 7.2
Embodiment 193 194 195 196 197 198 199 200
IC 50(nM) 4.5 18 1440 985 >10000 >10000 19 >10000
Embodiment 201 202 203 204 205 206 207 208
IC 50(nM) >10000 >10000 >10000 >10000 >10000 >10000 >10000 37
Embodiment 209 210 211 212 213 214 215 216
IC 50(nM) 103 10 145 19 58 517 1388 >10000
Embodiment 217 218 219 220 221 223 224 225
IC 50(nM) 2.5 103 481 >10000 >10000 >10000 1113 >10000
Embodiment 226 227 228 229 230 AZD2281 ABT-888 ?
IC 50(nM) 84 13 >10000 >10000 2.6 28 2642 ?
ND, does not determine.
Therefore, measure through cytoactive MTT detection method, 1-(3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone (embodiment 4) and its resemblance are to DNA damage kind anti-cancer drugs thing, and such as the T suppression cell accretion of methyl methylsulfonate (MMS) has good synergistic enhancing effect.
Embodiment 232
Application cell apoptotic proteins enzyme (Caspase)-3 enzymic activity measuring 1-(3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone and its resemblance are to the synergistic enhancing effect of the cell death inducing effect of methyl methylsulfonate (MMS)
People source breast cancer cell T47D is used to measure PARP-1 inhibitor to DNA damage kind anti-cancer drugs thing, the synergistic enhancing effect of the such as cell death inducing effect of methyl methylsulfonate (MMS).The vigor of intracellular apoptotic proteins enzyme (Caspase)-3 is used as and detects apoptotic index.In inducing cell, the MMS dose response effect of apoptotic proteins enzymic activity is through careful titration, only induces the MMS concentration of minimum apoptotic proteins enzymic activity to be used to detect the reinforcing effect of PARP inhibitor.In brief, DMEM/F12 (Hyclone) substratum is used to cultivate T47D cell containing 0.2U/mL Regular Insulin (Genview) and 10%FBS (Hyclone).Test the day before yesterday, with 20000 cells/well by T47D cell seeding to 96 porocyte culture plate, be placed in 37 DEG C at 5%CO 2incubator overnight incubation.Next day removes nutrient solution, and every hole adds the fresh culture of 180 μ L containing 100nM MMS (Sigma) respectively.Then positive compound (AZD2281 and ABT-888) or testing compound that 20 μ L contain 10 times of concentration is added.Positive compound and testing compound carry out continuous series dilution by 1:3 and 1:10 DMSO.The diluent of ten times of concentration is mixed with by 10 μ L DMSO diluents and 90 μ L fresh cultures and forms.After 24 hours, by culture plate in 1000g centrifugal 5 minutes, removing supernatant liquor, every hole adds 50 μ L cell pyrolysis liquid (Lysis Buffer:10mM Tris, pH7.5,0.1M NaCl, 1mM EDTA, 0.01%Triton X-100) 4 DEG C of horizontal oscillations 30 minutes.Then after centrifugal 10 minutes, draw 20 μ L supernatants respectively to corresponding 384 hole blackboards at 4 DEG C of 1000g from every hole, every hole adds 20 μ L containing 20 μMs of caspase-3 fluorogenic substrates ((Ac-DEVD) subsequently 2-R110, AnaSpec Cat#60304-5) damping fluid (20mMPIPES, pH7.4,4mM EDTA and 0.2%CHAPS).3 hours are hatched in 37 DEG C, fluorescence intensity (Varioskan Flash, Thermo Fisher Scientific) under ex:496nm, em:520nm after concussion mixing.The caspase-3 activity of compound induction is expressed with relative intensity of fluorescence (RFU).The Prism5 software of data analysis GraphPad company carries out.Data are by map to apoptotic proteins enzyme activity index fluorescence value with the compound concentration of logarithmetics and carry out curve equation model with following equations and draw EC 50value, Y (fluorescent value)=minimum fluorescence reading+(maximum fluorescence reading-minimum fluorescence reading)/(1+10^ (LogEC 50-LogC)), wherein C is test compounds substrate concentration.
Compound is to the EC of the synergistic enhancing effect of the induction T47D cells apoptosis of methyl methylsulfonate (MMS) 50value is summed up in table 2.
Form 2. replaces the synergistic enhancing effect (EC of 1-(arylmethyl) quinazoline-2,4 (1H, 3H)-diketone to the cell death inducing effect of MMS 50value)
Embodiment 1 2 3 4 5 6 7 8
EC 50(nM) >10000 >10000 56 12 450 2518 2655 120
Embodiment 9 10 11 12 13 14 15 16
EC 50(nM) 426 400 214 318 6601 39 803 9206
Embodiment 17 18 19 20 21 22 23 24
EC 50(nM) 5018 >10000 >10000 139 5797 >10000 4.0 20
Embodiment 25 26 27 28 29 30 31 32
EC 50(nM) 3.9 20 51 5894 >10000 39 112 96
Embodiment 33 34 35 36 37 38 39 40
EC 50(nM) 96 104 238 >10000 1914 267 614 29
Embodiment 41 42 43 44 45 46 47 48
EC 50(nM) 2.2 11 18 5.7 11 6.6 2.6 8.2
Embodiment 49 50 51 52 53 54 55 56
EC 50(nM) 10 13 20 22 18 124 20 16
Embodiment 57 58 59 60 61 62 63 64
EC 50(nM) 22 108 >10000 >10000 17 379 15 51
Embodiment 65 66 67 68 69 70 71 72
EC 50(nM) 373 604 4820 635 76 34 67 41
Embodiment 73 74 75 76 77 78 79 80
EC 50(nM) 811 2111 2869 ND 5206 112 3219 1192
Embodiment 81 82 83 84 85 86 87 88
EC 50(nM) 63 154 21 18 7.6 27 27 67
Embodiment 89 90 91 92 93 94 95 96
EC 50(nM) ND 4168 1987 2926 >10000 >10000 >10000 >10000
Embodiment 97 98 99 100 101 102 103 104
EC 50(nM) >10000 >10000 >10000 70 20 26 29 2.6
Embodiment 105 106 107 108 109 110 111 112
EC 50(nM) 14 217 9.5 68 23 32 1.7 2.9
Embodiment 113 114 115 116 117 118 119 120
EC 50(nM) 17 19 23 13 5.8 3.1 3.0 8.8
Embodiment 121 122 123 124 125 126 127 128
EC 50(nM) 4.9 8.4 11 3.8 22 6.5 4.1 12
Embodiment 129 130 131 132 133 134 135 136
EC 50(nM) 49 87 20 0.93 2.1 4.7 9.8 3.2
Embodiment 137 138 139 140 141 142 143 144
EC 50(nM) 2.1 281 4.0 8.9 13 3.8 6.0 3.4
Embodiment 145 146 147 148 149 150 151 152
EC 50(nM) 6.5 4.1 3.4 2.3 5.8 16 5.2 5.1
Embodiment 153 154 155 156 157 158 159 160
EC 50(nM) 2.0 6.7 12 14 26 8.6 220 261
Embodiment 161 162 163 164 165 166 167 168
EC 50(nM) 405 495 42 2.1 18 1.6 5.0 3.8
Embodiment 169 170 171 172 173 174 175 176
EC 50(nM) 1.0 43 23 3.2 122 37 14 10
Embodiment 177 178 179 180 181 182 183 184
EC 50(nM) 743 11 7.4 1.4 2.4 14 6.1 18
Embodiment 185 186 187 188 189 190 191 192
EC 50(nM) 2.1 6.8 30 ND ND ND ND 3.1
Embodiment 193 194 195 196 197 198 199 200
EC 50(nM) 1.6 11 471 >10000 >10000 >10000 4.9 >10000
Embodiment 201 202 203 204 205 206 207 208
EC 50(nM) >10000 >10000 >10000 >10000 >10000 >10000 >10000 24
Embodiment 209 210 211 212 213 214 215 216
EC 50(nM) 294 15 166 45 590 654 743 >10000
Embodiment 217 218 219 220 221 223 224 225
EC 50(nM) 19 37 445 >10000 >10000 >10000 274 >10000
Embodiment 226 227 228 229 230 AZD2281 ABT-888 ?
EC 50(nM) 24 40 >10000 >10000 3.2 24 3494 ?
ND, does not determine.
Therefore, apoptotic proteins enzyme assay 1-(3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2 in cell, 4 (1H, 3H)-diketone (embodiment 4) and its resemblance are to DNA damage kind anti-cancer drugs thing, and the such as cell death inducing effect of methyl methylsulfonate (MMS) has good synergistic enhancing effect.
Embodiment 233
The active MTT detection method of application cell detects 1-(3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2, the restraining effect that 4 (1H, 3H)-diketone and resemblance thereof increase the CAPAN-1 pancreatic cancer cell that BRCA-2 lacks
The cancer cell of BRCA disappearance is very responsive to PARP-1 inhibitor.Under the effect of PARP-1 inhibitor, the cell of BRCA disappearance is also final dead by stopping propagation.Selected being used for of the human pancreatic cancer cell CAPAN-1 of BRCA-2 disappearance detects the cell enlargement restraining effect replacing 1-(arylmethyl) quinazoline-2,4 (1H, 3H)-diketone.In brief, CAPAN-1 cultivates in the IMEM substratum containing 20%FBS, whole Therapy lasted 10 days.First day, evenly plants 6000 CAPAN-1 cells, is placed in 37 DEG C of CO2gas incubator and spends the night in 96 porocyte culture plates.Second day, carry out continuous series dilution with positive compound (AZD2281) and testing compound by 1:3 and 1:10 DMSO.The diluent of ten times of concentration is mixed with by 10 μ L DMSO diluents and 90 μ L fresh cultures and forms.Take out 96 porocyte culture plates, supernatant discarded, add the testing compound solution of 180 μ L fresh cultures and 20 μ L dilution, the ultimate density of DMSO is 1%.Then culture plate is put back to 37 DEG C of incubators and continue cultivation 2 days (the 3rd day and the 4th day).5th day, repeat second day same dispensing operation, supernatant discarded, added fresh substratum and testing compound, and then put into 37 DEG C of incubators and continue cultivation 2 days.8th day, repeat same dispensing operation, after supernatant discarded, add fresh culture, continue cultivation 2 days.Tenth day, every hole added MTT (5mg/mL) solution that 20 μ L configure, and continued cultivation 4 hours.Then remove supernatant, every hole adds 100 μ L DMSO, and level shakes 10 minutes.Then Varioskan Flash instrument (Thermo Fisher Scientific) is used to detect the absorption peak at 520 and 690nm place.Data processing GraphPad Prism5 has come.Data are mapped to the difference of 520/690nm reading by with the compound concentration of logarithmetics, and carry out curve equation model with following equations and draw IC 50value, Y (520nm-690nm)=minimal absorption value+(obtained the maximum absorption-minimal absorption value)/(1+10^ (LogC-LogIC 50)), C is test compounds substrate concentration.
Compound to the inhibiting rate of CAPAN-1 cell enlargement with IC 50represent, its value row in table 3.
Table 3 replaces the retarding effect (IC of 1-(arylmethyl) quinazoline-2,4 (1H, 3H)-diketone to CAPAN-1 cell enlargement 50value)
Embodiment 3 4 8 11 15 20 23 24
IC 50(nM) 445 55 2360 1841 >10000 4942 160 735
Embodiment 25 26 27 30 40 41 42 43
IC 50(nM) 98 400 281 1785 1739 208 2539 974
Embodiment 44 45 46 48 49 50 51 56
IC 50(nM) 318 668 446 168 421 173 402 1181
Embodiment 65 69 70 81 83 85 100 101
IC 50(nM) 3189 1982 339 421 746 291 312 1049
Embodiment 103 104 105 107 111 112 113 117
IC 50(nM) 665 452 97 161 77 767 170 39
Embodiment 118 119 123 124 127 128 132 133
IC 50(nM) 54 56 111 137 44 442 17 22
Embodiment 134 136 139 140 142 143 144 145
IC 50(nM) 45 40 36 155 223 73 78 146
Embodiment 147 149 150 152 154 155 157 161
IC 50(nM) 47 52 176 121 56 142 202 3547
Embodiment 168 172 176 185 186 188 189 190
IC 50(nM) 1465 389 187 358 167 472 736 1383
Embodiment 199 210 212 217 AZD2281 ? ? ?
IC 50(nM) 25 948 3445 >10000 460 ? ? ?
Therefore, 1-(3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone (embodiment 4) and the growth of resemblance to CAPAN-1 cell thereof have good restraining effect, are good PARP-1 inhibitor.
Embodiment 234
Application PARP-1 enzymic activity measuring 1-(3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone and its resemblance are to the retarding effect of PARP-1 enzymic activity
The test of PARP-1 enzymic activity is the 96 hole chemical luminescence reagent kits (4676-096-K, Trevigen, Inc.Gaithersburg, MD 20877USA) adopting Trevigen company.In simple terms, poly-(the ADP-ribose) of PARP-1 catalysis dependence NAD adds its nucleoprotein substrate, such as histone to.Test kit 96 hole pattern tests have biotin labeled poly-(ADP-ribose) to join on histone.
Positive compound (AZD2281) and testing compound carry out continuous series dilution by 1:10 1X damping fluid.In the hole being attached with histone accordingly, add positive compound or testing compound that 10 μ L contain 5 times of concentration, the PARP enzyme total amount of 15 μ L is Mei Kong 0.5 unit and 25 μ L reaction solutions.Cultivating incubated at room 60 minutes.To wash twice with the washings that 200 μ LPBS add 0.1%Triton X-100 afterwards and 200 μ L PBS wash twice.Removing surplus liquid gently knocked by paper handkerchief.With equal-volume mixing PeroxyGlow tMafter solution A and B, after every hole adds 100 μ L, putting into Varioskan Flash microplate reader (Thermo Fisher Scientific) carries out chemiluminescence readings at once.The Prism5 software of data analysis GraphPad company carries out.Data are by map to chemiluminescence readings with the compound concentration of logarithmetics and carry out curve equation model with following equations and draw IC 50value, Y (values of chemiluminescence)=minimum luminous value+(maximum luminous value-minimum luminous value)/(1+10^ (LogC-LogIC 50)), C is test compounds substrate concentration
Compound is to the IC of the retarding effect of PARP-1 enzymic activity 50value is summarised in form 4.
Form 4. replaces the retarding effect (IC of 1-(arylmethyl) quinazoline-2,4 (1H, 3H)-diketone to PARP-1 enzymic activity 50value)
Embodiment 3 4 8 14 25 44 127 132 135 139
IC 50(nM) 4.2 0.96 5.3 2.3 0.21 0.88 0.37 1.19 1.74 1.3
Embodiment 144 147 189 AZD2281 ? ? ? ? ? ?
IC 50(nM) 1.15 1.2 2.20 2.2 ? ? ? ? ? ?
Therefore, through PARP-1 enzymic activity measuring 1-(3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone (embodiment 4) and its resemblance are good PARP-1 inhibitor.
Although adequately describe the present invention, it will be appreciated by those skilled in the art that and when not affecting the scope of the invention or its any embodiment, identical enforcement can be carried out in extensive and equivalent condition, preparation and other parameter area.The all patents quoted herein, patent application and publication are all incorporated herein by reference.

Claims (17)

1. the compound of formula I, or its pharmacologically acceptable salt or prodrug:
Wherein, Ar be between position have aryl or the heteroaryl of substituted carbonyl or methyl;
R 1-R 6independent is hydrogen, halogen, the amino that can be substituted, the alkoxyl group that can be substituted, the C that can be substituted 1-10the alkylthio that alkyl, alkylhalide group, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, ethylidene dioxy base, nitro, cyano group, amide group, hydroxyl, sulfydryl, acyloxy, azido-, carboxyl, oxyamide base maybe can be substituted.
2. the compound of claim 1, wherein R 5and R 6hydrogen, Ar be between position have the phenyl of substituted carbonyl, pyridyl or furyl.
3. the compound of claim 1 is wherein the compound of formula II, or its pharmacologically acceptable salt or prodrug:
Wherein, R 1-R 4independent is hydrogen, halogen, the amino that can be substituted, the alkoxyl group that can be substituted, the C that can be substituted 1-10the alkylthio that alkyl, alkylhalide group, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, nitro, ethylidene dioxy base, cyano group, amide group, hydroxyl, sulfydryl, acyloxy, azido-, carboxyl, oxyamide base maybe can be substituted;
R 7-R 10independent is hydrogen, halogen, the amino that can be substituted, alkoxyl group, C 1-10alkyl, alkylhalide group, aryl, heteroaryl, carbocylic radical, heterocyclic radical, alkenyl, alkynyl, arylalkyl, aromatic yl alkenyl, aromatic yl polysulfide yl, heteroarylalkyl, heteroarylalkenyl groups, heteroaryl alkynyl, carbocyclic ring alkyl, Heterocyclylalkyl, hydroxyalkyl, hydroxy alkoxy base, aminoalkyl, amido alkoxyl group, carboxyalkyl, Carboxyalkoxy, nitro, cyano group, amide group, aminocarboxyl, hydroxyl, sulfydryl, acyloxy, azido-, carboxyl, oxyamide base, alkyl sulphonyl, amido alkylsulfonyl, two substituted alkyl amido alkylsulfonyls, alkyl sulphinyl, alkylthio, or the carbonyl replaced,
R 11for amino, diazanyl, alkoxyl group, the C that can be substituted 1-10alkyl, alkylhalide group, aryl, heteroaryl, carbocylic radical, heterocyclic radical, alkenyl, alkynyl, arylalkyl, aromatic yl alkenyl, aromatic yl polysulfide yl, heteroarylalkyl, heteroarylalkenyl groups, heteroaryl alkynyl, carbocyclic ring alkyl, Heterocyclylalkyl, hydroxyalkyl, hydroxy alkoxy base, aminoalkyl, amido alkoxyl group, carboxyalkyl, Carboxyalkoxy, amide group, hydroxyl, sulfydryl, acyloxy, oxyamide base or alkylthio.
4. the compound of claim 1 is wherein the compound of formula III, or its pharmacologically acceptable salt or prodrug:
Wherein, R 1-R 4independent is hydrogen, halogen, the amino that can be substituted, the alkoxyl group that can be substituted, the C that can be substituted 1-10the alkylthio that alkyl, alkylhalide group, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, nitro, cyano group, ethylidene dioxy base, amide group, hydroxyl, sulfydryl, acyloxy, azido-, carboxyl, oxyamide base maybe can be substituted;
R 7-R 10independent is hydrogen, halogen, the amino that can be substituted, alkoxyl group, C 1-10alkyl, alkylhalide group, aryl, carbocylic radical, heterocyclic radical, heteroaryl, alkenyl, alkynyl, arylalkyl, aromatic yl alkenyl, aromatic yl polysulfide yl, heteroarylalkyl, heteroarylalkenyl groups, heteroaryl alkynyl, carbocyclic ring alkyl, Heterocyclylalkyl, hydroxyalkyl, hydroxy alkoxy base, aminoalkyl, amido alkoxyl group, carboxyalkyl, Carboxyalkoxy, nitro, cyano group, amide group, aminocarboxyl, hydroxyl, sulfydryl, acyloxy, azido-, carboxyl, oxyamide base, alkyl sulphonyl, amido alkylsulfonyl, two substituted alkyl amido alkylsulfonyls, alkyl sulphinyl, alkylthio, or the carbonyl replaced,
R 12for the C that can be substituted 1-10alkyl, alkylhalide group, cycloalkyl, aryl, heteroaryl, carbocylic radical, heterocyclic radical, alkenyl, alkynyl, arylalkyl, aromatic yl alkenyl, aromatic yl polysulfide yl, heteroarylalkyl, heteroarylalkenyl groups, heteroaryl alkynyl, carbocyclic ring alkyl, Heterocyclylalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, alkyl-carbonyl, acyl group, naphthene base carbonyl, aryl carbonyl, Heteroarylcarbonyl, Heterocyclylcarbonyl, amino-carbonyl, alkyl sulphonyl, naphthene sulfamide base or amido alkylsulfonyl.
5. the compound of claim 4, wherein R 1or R 2hydrogen, fluorine, chlorine, bromine or methyl; R 4hydrogen, fluorine, methyl, methoxyl group or hydroxyl; R 7, R 8, R 9or R 10hydrogen or fluorine.
6. the compound of claim 4, wherein R 12cycloalkyl, aryl, heteroaryl, carbocylic radical, heterocyclic radical, arylalkyl, heteroarylalkyl, carbocyclic ring alkyl, Heterocyclylalkyl, alkyl-carbonyl, naphthene base carbonyl, aryl carbonyl, Heteroarylcarbonyl or Heterocyclylcarbonyl.
7. the compound of claim 1, wherein said compound is selected from:
1-(3-methoxycarbonyl benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(3-carboxybenzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(3-(4-(pyridine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(3-(4-cyclohexylpiperazin-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(3-(4-([1,2,4] triazolo [4,3-b] pyridazine-6-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(3-(4-ethyl piperazidine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(3-(4-benzoyl piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(3-(4-(4-fluorobenzoyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(3-(4-(4-chlorobenzoyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(3-(4-(4-Bromophenacyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(3-(4-(4-methoxybenzoyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(3-(4-(tetrahydrochysene-2H-pyrans-4-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(3-(4-(cyclopentylcarbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(3-(4-(cyclopropyl carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(3-(4-ethylsulfonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(3-(4-Acetylpiperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(3-(4-Phenylpiperidine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(3-(4-phenylpiperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(3-(4-(pyrazine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(the fluoro-3-methoxycarbonyl benzyl of 4-) quinazoline-2,4 (1H, 3H)-diketone;
1-(3-carbonyl-4-luorobenzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(the fluoro-3-of 4-(4-cyclopentylcarbonyl piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(the fluoro-3-of 4-(4-(pyridine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(the fluoro-3-of 4-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(3-(4-(cyclohexyl-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(3-(4-(benzo [d] isothiazole-3-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(3-(4-(piperidin-1-yl) piperidines-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(3-(4-(pyridin-4-yl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(3-(4-(cyclobutyl carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(3-(4-(6-fluorobenzene is [d] isoxzzole-3-base also) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(3-(4-(thiophene-2-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(3-(4-(furans-2-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(3-(4-(furans-3-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(3-(4-(thiophene-3-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(3-(4-(pyridine-3-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(3-(4-(pyridine-2-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(3-(4-(pyridine-4-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(3-(4-Phenoxypiperidines-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(the fluoro-3-of 4-(4-(cyclopropyl carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(the fluoro-3-of 4-(4-(cyclohexyl-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(the fluoro-3-of 4-(4-(pyrazine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(the fluoro-3-of 4-(4-(benzo [d] isothiazole-3-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(the fluoro-3-of 4-(4-(cyclobutyl carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(the fluoro-3-of 4-(4-benzoyl piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(the fluoro-3-of 4-(4-(thiophene-2-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(the fluoro-3-of 4-(4-(furans-2-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(the fluoro-3-of 6-(4-(cyclopentylcarbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(the fluoro-3-of 6-(4-(cyclohexyl-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(the fluoro-3-of 6-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(the fluoro-3-of 6-(4-(pyridine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(the fluoro-3-of 6-(4-(thiophene-2-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(the fluoro-3-of 6-(4-(cyclobutyl carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(the fluoro-3-of 6-(4-(furans-2-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(the chloro-3-of 6-(4-(cyclopentylcarbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone
1-(the chloro-3-of 6-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(the chloro-3-of 6-(4-(cyclohexyl-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(the chloro-3-of 6-(4-(pyridine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(the chloro-3-of 2-(4-(cyclopentylcarbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(the chloro-3-of 2-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(the fluoro-3-of 2-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(the fluoro-3-of 2-(4-(cyclopentylcarbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(the fluoro-3-of 5-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(the fluoro-3-of 5-(4-(cyclopentylcarbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(the chloro-3-of 4-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(the chloro-3-of 4-(4-(cyclohexyl-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-((2-(4-(cyclopentylcarbonyl) piperazine-1-carbonyl) furans-5-base) methyl) quinazoline-2,4 (1H, 3H)-diketone;
1-((2-(4-(benzo [d] isothiazole-3-base) piperazine-1-carbonyl) furans-5-base) methyl) quinazoline-2,4 (1H, 3H)-diketone;
1-((2-(4-(cyclopentylcarbonyl) piperazine-1-carbonyl) pyridine-6-base) methyl) quinazoline-2,4 (1H, 3H)-diketone;
1-((2-(4-(pyridine-2-base) piperazine-1-carbonyl) pyridine-6-base) methyl) quinazoline-2,4 (1H, 3H)-diketone;
1-((2-(4-(pyrimidine-2-base) piperazine-1-carbonyl) pyridine-6-base) methyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(3-(4-(thiazol-2-yl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(3-(4-(cyclohexyl methyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(3-(4-(cyclopentyl-methyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(3-(4-(cyclohexylsulfonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 7-(3-(4-(cyclopentylcarbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 7-(3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
7-methyl isophthalic acid-(3-(4-(cyclopentylcarbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
7-methyl isophthalic acid-(3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
6-methyl isophthalic acid-(3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
6-methyl isophthalic acid-(3-(4-(cyclopentylcarbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
6-methyl isophthalic acid-(the fluoro-3-of 4-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
6-methyl isophthalic acid-(the fluoro-3-of 4-(4-(cyclohexyl-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
6-methyl isophthalic acid-(the fluoro-3-of 4-(4-(cyclopentylcarbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The bromo-1-of 6-(3-(4-(cyclohexyl-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The bromo-1-of 6-(3-(4-(cyclopentylcarbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The bromo-1-of 6-(3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
6-nitro-1-(3-(4-(cyclopentylcarbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
6-nitro-1-(3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
6-nitro-1-(3-(4-(cyclohexyl-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The chloro-1-of 5-(3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The chloro-1-of 5-(3-(4-(cyclopentylcarbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The chloro-1-of 5-(3-(4-(cyclohexyl-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The chloro-1-of 5-(the fluoro-3-of 4-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The chloro-1-of 5-(the fluoro-3-of 4-(4-(cyclopentylcarbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The chloro-1-of 5-(the fluoro-3-of 4-(4-(cyclohexyl-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The chloro-1-of 5-(the fluoro-3-of 4-(4-(pyridine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The chloro-1-of 5-(the fluoro-3-of 4-(4-(thiophene-2-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The chloro-1-of 5-(the fluoro-3-of 6-(4-(cyclohexyl-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The chloro-1-of 5-(the fluoro-3-of 6-(4-(cyclopentylcarbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The chloro-1-of 5-(the fluoro-3-of 6-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The chloro-1-of 6-(3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The chloro-1-of 6-(3-(4-(cyclopentylcarbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The chloro-1-of 6-(3-(4-(cyclohexyl-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The chloro-1-of 6-(3-(4-(pyridine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The chloro-1-of 6-(3-(4-(thiophene-2-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The chloro-1-of 6-(3-(4-(cyclobutyl carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The chloro-1-of 6-(the fluoro-3-of 4-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The chloro-1-of 6-(the fluoro-3-of 4-(4-(cyclopentylcarbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The chloro-1-of 6-(the fluoro-3-of 4-(4-(cyclohexyl-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The chloro-1-of 6-(the fluoro-3-of 4-(4-(pyridine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The chloro-1-of 6-(the fluoro-3-of 4-(4-(thiophene-2-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The chloro-1-of 6-(the fluoro-3-of 4-(4-(cyclopropyl carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The chloro-1-of 6-(the fluoro-3-of 6-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The chloro-1-of 6-(the fluoro-3-of 6-(4-(cyclopentylcarbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The chloro-1-of 6-(the fluoro-3-of 6-(4-(cyclohexyl-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The chloro-1-of 6-(the fluoro-3-of 6-(4-(thiophene-2-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 5-(3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 5-(3-(4-(cyclopentylcarbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 5-(3-(4-(cyclohexyl-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 5-(3-(4-(pyridine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 5-(3-(4-(thiophene-2-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 5-(the fluoro-3-of 4-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 5-(the fluoro-3-of 4-(4-(cyclopentylcarbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 5-(the fluoro-3-of 4-(4-(cyclohexyl-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 5-(the fluoro-3-of 4-(4-(pyridine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 5-(the fluoro-3-of 4-(4-(thiophene-2-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 5-(the fluoro-3-of 4-(4-benzoyl piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 8-(3-(4-(cyclohexyl-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 6-(3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 6-(3-(4-(pyridine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 6-(3-(4-(thiophene-2-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 6-(3-(4-(cyclohexyl-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 6-(3-(4-(cyclopentylcarbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 6-(the fluoro-3-of 4-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 6-(the fluoro-3-of 4-(4-(pyridine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 6-(the fluoro-3-of 4-(4-(thiophene-2-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 6-(the fluoro-3-of 4-(4-(cyclohexyl-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 6-(the fluoro-3-of 4-(4-(cyclopentylcarbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 6-(the fluoro-3-of 6-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 6-(the fluoro-3-of 6-(4-(pyridine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 6-(the fluoro-3-of 6-(4-(thiophene-2-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 6-(the fluoro-3-of 6-(4-(cyclohexyl-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 6-(the fluoro-3-of 6-(4-(cyclopentylcarbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 5-(the fluoro-3-of 6-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 5-(the fluoro-3-of 6-(4-(pyridine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 5-(the fluoro-3-of 6-(4-(thiophene-2-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 5-(the fluoro-3-of 6-(4-(cyclohexyl-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 5-(the fluoro-3-of 6-(4-(cyclopentylcarbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
5-methyl isophthalic acid-(3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
5-methyl isophthalic acid-(3-(4-(cyclopentylcarbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The chloro-1-of 7-(3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The chloro-1-of 7-(3-(4-(cyclopentylcarbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 5-(the fluoro-3-of 4-(4-(cyclopropyl carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The chloro-1-of 6-(the fluoro-3-of 4-(4-benzoyl piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 5-(3-(4-(cyclobutyl carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 5-(the fluoro-3-of 4-(4-(cyclobutyl carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The chloro-1-of 6-(the fluoro-3-of 6-(4-(cyclobutyl carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The chloro-1-of 5-(the fluoro-3-of 4-(4-(cyclobutyl carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The chloro-1-of 6-(the fluoro-3-of 4-(4-(cyclobutyl carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The chloro-1-of 5-(the fluoro-3-of 6-(4-(cyclobutyl carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The chloro-1-of 5-(the fluoro-3-of 6-(4-(thiophene-2-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 5-(the fluoro-3-of 4-(4-(furans-2-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The chloro-1-of 5-(the fluoro-3-of 6-(4-(pyridine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The chloro-1-of 6-(the fluoro-3-of 6-(4-(pyridine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The chloro-1-of 6-(the fluoro-3-of 5-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 5-(the fluoro-3-of 5-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(3-(4-cyclopentyl-based piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 6-(the fluoro-3-of 4-(4-(cyclopropyl carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 6-(3-(4-(cyclobutyl carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 6-(the fluoro-3-of 4-(4-(cyclobutyl carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 6-(the fluoro-3-of 4-(4-benzoyl piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 5-(the fluoro-3-of 6-(4-(cyclobutyl carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 6-(the fluoro-3-of 6-(4-(cyclobutyl carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 5-(the fluoro-3-of 6-(4-(furans-2-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 6-(the fluoro-3-of 4-(4-(furans-2-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 6-(the fluoro-3-of 5-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 6-(the chloro-3-of 6-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 6-(the fluoro-3-of 4-(4-(thiazol-2-yl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 5-(the fluoro-3-of 4-(4-(thiazol-2-yl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(the fluoro-3-of 4-(4-(thiazol-2-yl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(3-(4-(cyclohexyl carboxyamide base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
1-(the fluoro-3-of 4-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-dione hydrochloride;
The fluoro-1-of 5-(the fluoro-3-of 4-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-dione hydrochloride;
1-(3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-dione hydrochloride;
1-(3-([1,2,4] triazole [4,3-a] pyridine-6-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 6-((2-(4-(pyrimidine-2-base) piperazine-1-carbonyl) pyridine-6-base) methyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 5-(the fluoro-3-of 4-(4-methoxYbenzylamino formyl radical) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 5-(the fluoro-3-of 4-(3-chlorobenzylcarbamoyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 5-(the fluoro-3-of 4-(carbamovl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
5-methoxyl group-1-(3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
6-methoxyl group-1-(3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 5-(the fluoro-3-of 4-(5-bromo pyrimi piperidine-2-carbamoylamino) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
7-Trifluoromethyl-1-(3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
6,7-ethylene Oxy-1-(3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 5-(6-methoxyl group-3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
7-methoxyl group-1-(3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 5-(the fluoro-3-of 4-(4-(tetrahydrofuran (THF)-2-carbonyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 5-(4-nitro-3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 5-(the fluoro-3-of 4-(4-cyclohexylpiperazin-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 5-(the fluoro-3-of 4-(4-phenylpiperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 5-(the fluoro-3-of 4-(4-Phenylpiperidine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 5-(the bromo-3-of 4-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
6,7-methylenedioxy-1-(3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 5-(the fluoro-3-of 4-(4-(cyclohexyl methyl) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The fluoro-1-of 8-(3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
6-amino-1-(3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
The chloro-1-of 8-(3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
8-methyl isophthalic acid-(3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
8-methoxyl group-1-(3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
8-hydroxyl-1-(3-(4-(pyrimidine-2-base) piperazine-1-carbonyl) benzyl) quinazoline-2,4 (1H, 3H)-diketone;
Or its pharmacologically acceptable salt or prodrug.
8. the purposes of the compound according to any one of claim 1 ~ 7 in the medicine of the disease that preparation is treated or prevention causes because PARP activity is abnormal.
9. the purposes of claim 8, wherein said disease is cancer.
10. the purposes of claim 9, wherein said cancer is liver cancer, melanoma, Hodgkin's disease, non-Hodgkin lymphoma, acute lymphatic leukaemia, chronic lymphocytic leukemia, multiple myeloma, neuroblastoma, mammary cancer, ovarian cancer, lung cancer, wilms' tumor, cervical cancer, carcinoma of testis, soft tissue sarcoma, chronic lymphocytic leukemia, primary macroglobulinaemia, wing indulges in cancer, chronic myelocytic leukemia, primary brain cancer, malignant melanoma, small cell lung cancer, cancer of the stomach, colorectal carcinoma, malignant pancreatic insulinoma, malignant carcinoid carcinomas, malignant melanoma, choriocarcinoma, gill fungus Sample Rou Ya Swollen, head or neck cancer, osteogenic sarcoma, carcinoma of the pancreas, acute myeloblastic leukemia, hairy cell leukemia, rhabdosarcoma, Kaposi sarcoma, urogenital neoplasm, thyroid carcinoma, the esophageal carcinoma, malignant hypercalcemia, hyperplasia of cervix uteri disease, renal cell carcinoma, carcinoma of endometrium, polycythemia vera, essential thrombocythemia, adrenocortical carcinoma, skin carcinoma or prostate cancer.
The purposes of 11. claims 10, wherein institute's drug also comprises the known cancer therapy drug of at least one, or the pharmacologically acceptable salt of described cancer therapy drug.
The purposes of 12. claims 10, wherein institute's drug comprises the cancer therapy drug that at least one is selected from lower group: busulfan, melphalan, Chlorambucil, endoxan, ifosfamide, Temozolomide, bendamustine, cis-platinum, ametycin, bleomycin, carboplatin, camptothecine, irinotecan, Hycamtin, Zorubicin, pidorubicin, aclacinomycin, mitoxantrone, NSC-264137, inscription holder pool is general, born of the same parents are general for 5-azepine, gemcitabine, 5-fluorine urine is crowed and is suck, first atmosphere butterfly is chanted, the fluoro-2'-uracil deoxyriboside of 5-, fludarabine, Nelzarabine, cytosine arabinoside, sulphur bird throat chants, Pralatrexate, pemetrexed, hydroxyurea, thioguanine, colchicine, vinealeucoblastine(VLB), vincristine(VCR), vinorelbine, taxol, ipsapirone, Cabazitaxel, docetaxel, monoclonal antibody (campath), Victibix, Ofatumumab, Avastin, Trastuzumab, Mabthera, imatinib, Gefitinib, erlotinib, lapatinibditosylate, Xarelto, Sutent, nilotinib, Dasatinib, pazopanib, special cancer is fitted, everolimus, Vorinostat, sieve miaow ester peptide, tamoxifen, letrozole, fulvestrant, mitoguazone, Sostatin, vitamin A acid, arsenic, Zoledronic acid, Velcade, Sa Li polyamines or Revlimid.
The purposes of 13. claims 10, wherein said medicine and radiotherapy coupling.
14. purposes as claimed in claim 10, it is characterized in that, described disease is central nervous system disease, comprises apoplexy and nerve degenerative diseases.
15. 1 kinds of medicinal compositionss, comprise the compound according to any one of claim 1 ~ 7 and pharmaceutically acceptable carrier.
The medicinal compositions of 16. claims 15, wherein said composition is also containing the cancer therapy drug that at least one is known, or the pharmacologically acceptable salt of described cancer therapy drug.
The medicinal compositions of 17. claims 15, wherein, described composition is also selected from the cancer therapy drug of lower group containing at least one: busulfan, melphalan, Chlorambucil, endoxan, ifosfamide, Temozolomide, bendamustine, cis-platinum, ametycin, bleomycin, carboplatin, camptothecine, irinotecan, Hycamtin, Zorubicin, pidorubicin, aclacinomycin, mitoxantrone, NSC-264137, inscription holder pool is general, born of the same parents are general for 5-azepine, gemcitabine, 5-fluorine urine is crowed and is suck, first atmosphere butterfly is chanted, the fluoro-2'-uracil deoxyriboside of 5-, fludarabine, Nelzarabine, cytosine arabinoside, sulphur bird throat chants, Pralatrexate, pemetrexed, hydroxyurea, thioguanine, colchicine, vinealeucoblastine(VLB), vincristine(VCR), vinorelbine, taxol, ipsapirone, Cabazitaxel, docetaxel, monoclonal antibody (campath), Victibix, Ofatumumab, Avastin, Trastuzumab, Mabthera, imatinib, Gefitinib, erlotinib, lapatinibditosylate, Xarelto, Sutent, nilotinib, Dasatinib, pazopanib, special cancer is fitted, everolimus, Vorinostat, sieve miaow ester peptide, tamoxifen, letrozole, fulvestrant, mitoguazone, Sostatin, vitamin A acid, arsenic, Zoledronic acid, Velcade, Sa Li polyamines or Revlimid.
CN201410398758.5A 2011-04-01 2012-03-31 1-(aryl methyl) quinazoline-2,4 (1H, 3H)-diketone is as PARP inhibitor and application thereof Active CN104230827B (en)

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CN201110082475.6 2011-04-01
CN2011100824756A CN102731416A (en) 2011-04-01 2011-04-01 1-(aryl methyl)-quinazoline-2,4-dione as PARP inhibitor and its application
CN2011100824756 2011-04-01
CNPCT/CN2011/077034 2011-07-11
CN2011077034 2011-07-11
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016155655A1 (en) * 2015-04-03 2016-10-06 上海瑛派药业有限公司 Solid pharmaceutical dosage form of parp inhibitor, and application of solid pharmaceutical dosage form of parp inhibitor
WO2022199697A1 (en) * 2021-03-26 2022-09-29 Impact Therapeutics (Shanghai) , Inc Oral capsule of parp inhibitor and preparation method thereof

Families Citing this family (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012125521A1 (en) 2011-03-14 2012-09-20 Eternity Bioscience Inc. Quinazolinediones and their use
TWI527800B (en) 2011-04-01 2016-04-01 南京英派藥業有限公司 1-(arylmethyl)quinazoline-2,4(1h,3h)-diones as parp inhibitors and the use thereof
WO2013064083A1 (en) 2011-11-01 2013-05-10 Impact Therapeutics, Inc. 1-(arylmethyl)-5,6,7,8-tetrahydroquinazoline-2,4-diones and analogs and the use thereof
BR112014026266A2 (en) 2012-04-24 2017-06-27 Chugai Pharmaceutical Co Ltd quinazolidinedione derivative
SG11201406860SA (en) 2012-04-24 2014-11-27 Chugai Pharmaceutical Co Ltd Quinazolinedione derivative
PE20160122A1 (en) 2013-03-13 2016-02-12 Forma Therapeutics Inc NOBLE COMPOUNDS AND COMPOSITIONS FOR INHIBITION OF FASN
AU2014338070A1 (en) 2013-10-23 2016-05-05 Chugai Seiyaku Kabushiki Kaisha Quinazolinone and isoquinolinone derivative
WO2016016267A1 (en) * 2014-07-28 2016-02-04 Technische Universität Dresden Efficient inhibition of hsp27
CN106083741A (en) * 2016-02-22 2016-11-09 南京中医药大学 2 sulfur are for quinazolinedione derivatives
CN107098886B (en) * 2016-02-26 2020-07-14 中国医学科学院药物研究所 Prazinone-containing quinazolinone PARP-1/2 inhibitor and preparation method, pharmaceutical composition and application thereof
US10722484B2 (en) 2016-03-09 2020-07-28 K-Gen, Inc. Methods of cancer treatment
EP3438096B1 (en) * 2016-04-01 2020-12-02 Impact Therapeutics, Inc Manufacturing process for 1-(arylmethyl) quinazoline-2,4 (1h, 3h)-dione
CN108727343A (en) * 2017-04-21 2018-11-02 中国医学科学院药物研究所 Quinazolinones PARP-1/2 inhibitor containing 3- amino nafoxidines and preparation method thereof, pharmaceutical composition and purposes
TWI767148B (en) 2018-10-10 2022-06-11 美商弗瑪治療公司 Inhibiting fatty acid synthase (fasn)
CN113382633A (en) 2018-10-29 2021-09-10 福马治疗股份有限公司 Solid forms of (4- (2-fluoro-4- (1-methyl-1H-benzo [ d ] imidazol-5-yl) benzoyl) piperazin-1-yl) (1-hydroxycyclopropyl) methanone
CN111269216A (en) * 2018-12-05 2020-06-12 中国医学科学院药物研究所 Piperazinone-containing quinazoline dione compound, preparation method, pharmaceutical composition and application thereof
CN114206864B (en) * 2019-05-14 2024-05-24 苏州四体康宸医药科技有限公司 Quinazoline-2, 4-dione derivatives as PARP inhibitors
CN116322680A (en) * 2020-07-24 2023-06-23 上海瑛派药业有限公司 Combination regimens for PARP inhibitors
WO2022099442A1 (en) * 2020-11-10 2022-05-19 上海瑛派药业有限公司 Crystalline forms of 5-fluoro-1-(4-fluoro-3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1h,3h)-dione and preparation therefor
WO2023138667A1 (en) * 2022-01-21 2023-07-27 上海瑛派药业有限公司 Compound preparation of senaparib and temozolomide and preparation method therefor

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2652144A1 (en) * 1976-11-16 1978-05-18 Merck Patent Gmbh Quinazoline:di:one derivs. - useful as analgesics, antiinflammatory agents and sedatives
JP2001302515A (en) * 2000-04-18 2001-10-31 Sumitomo Pharmaceut Co Ltd Poly(adp-ribose)polymerase inhibitor
JP2002284699A (en) * 2001-03-28 2002-10-03 Sumitomo Pharmaceut Co Ltd Curative for visual cell degenerative disease
WO2006003148A1 (en) * 2004-06-30 2006-01-12 Janssen Pharmaceutica N.V. Quinazolinedione derivatives as parp inhibitors
JP2007137818A (en) * 2005-11-17 2007-06-07 Taisho Pharmaceut Co Ltd 8-hydroxy-2,4(1h,3h)-quinazolinedione derivative

Family Cites Families (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3989816A (en) 1975-06-19 1976-11-02 Nelson Research & Development Company Vehicle composition containing 1-substituted azacycloheptan-2-ones
US4444762A (en) 1980-04-04 1984-04-24 Nelson Research & Development Company Vehicle composition containing 1-substituted azacyclopentan-2-ones
CA1161036A (en) 1980-05-15 1984-01-24 Masayuki Ishikawa Quinazoline-dione compounds, process for production thereof and pharmaceutical use thereof
WO1988001270A1 (en) 1986-08-21 1988-02-25 Pfizer Inc. Pyridopyrimidinediones
DE69622148T2 (en) 1995-09-28 2002-10-31 Suntory Ltd Osaka CHINAZOZINE DERIVATIVES AND THEIR USE
US6201121B1 (en) 1995-12-28 2001-03-13 Fuji Chemical Industry Co., Ltd. Process for the preparation of 3-dihalobenzyl-2,4-quinazolinedione derivatives
AU1743997A (en) 1996-12-20 1998-07-17 Geron Corporation Poly(adp-ribose) polymerase inhibitors to treat diseases associated with cellular senescence
AUPO440496A0 (en) * 1996-12-30 1997-01-23 Fujisawa Pharmaceutical Co., Ltd. Quinazoline derivatives
KR20000075934A (en) 1997-03-17 2000-12-26 후지야마 아키라 Process for producing quinazoline derivatives
AU2002302894A1 (en) * 2001-06-19 2003-01-02 Warner-Lambert Company Llc Quinazolinediones as antibacterial agents
DE10201240A1 (en) 2002-01-15 2003-07-24 Bayer Ag New 1-substituted fused bicyclic uracil derivatives, are poly-(ADP-ribose) synthase inhibitors useful for treating e.g. ischemia, reperfusion damage, cardiovascular diseases, arthritis, asthma and neurodegenerative diseases
WO2008150470A1 (en) 2007-05-31 2008-12-11 Shionogi & Co., Ltd. Oxyimino compounds and the use thereof
GB0716532D0 (en) 2007-08-24 2007-10-03 Angeletti P Ist Richerche Bio Therapeutic compounds
ES2367760T3 (en) 2008-03-27 2011-11-08 Janssen Pharmaceutica, N.V. DERIVATIVES OF QUINAZOLINONA AS INHIBITORS OF THE POLYMERIZATION OF THE TUBULIN.
US20140018376A1 (en) * 2009-10-20 2014-01-16 Hans Allgeier Use of 1H-Quinazoline-2,4-Diones
WO2012125521A1 (en) * 2011-03-14 2012-09-20 Eternity Bioscience Inc. Quinazolinediones and their use
TWI527800B (en) 2011-04-01 2016-04-01 南京英派藥業有限公司 1-(arylmethyl)quinazoline-2,4(1h,3h)-diones as parp inhibitors and the use thereof

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2652144A1 (en) * 1976-11-16 1978-05-18 Merck Patent Gmbh Quinazoline:di:one derivs. - useful as analgesics, antiinflammatory agents and sedatives
JP2001302515A (en) * 2000-04-18 2001-10-31 Sumitomo Pharmaceut Co Ltd Poly(adp-ribose)polymerase inhibitor
JP2002284699A (en) * 2001-03-28 2002-10-03 Sumitomo Pharmaceut Co Ltd Curative for visual cell degenerative disease
WO2006003148A1 (en) * 2004-06-30 2006-01-12 Janssen Pharmaceutica N.V. Quinazolinedione derivatives as parp inhibitors
JP2007137818A (en) * 2005-11-17 2007-06-07 Taisho Pharmaceut Co Ltd 8-hydroxy-2,4(1h,3h)-quinazolinedione derivative

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016155655A1 (en) * 2015-04-03 2016-10-06 上海瑛派药业有限公司 Solid pharmaceutical dosage form of parp inhibitor, and application of solid pharmaceutical dosage form of parp inhibitor
CN107405349A (en) * 2015-04-03 2017-11-28 上海瑛派药业有限公司 PARP inhibitor solid pharmaceutical dosage formulation and its application
AU2016239141B2 (en) * 2015-04-03 2019-04-18 Impact Therapeutics (Shanghai), Inc Solid pharmaceutical formulation of PARP inhibitors and the use thereof
CN107405349B (en) * 2015-04-03 2021-03-02 上海瑛派药业有限公司 Solid pharmaceutical dosage form of PARP inhibitor and application thereof
US11179392B2 (en) 2015-04-03 2021-11-23 Impact Therapeutics, Inc. Solid pharmaceutical formulation of PARP inhibitors and use thereof
WO2022199697A1 (en) * 2021-03-26 2022-09-29 Impact Therapeutics (Shanghai) , Inc Oral capsule of parp inhibitor and preparation method thereof

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